PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of ijadInternational Journal of Alzheimer's Disease
 
Int J Alzheimers Dis. 2010; 2010: 604792.
Published online 2010 December 2. doi:  10.4061/2010/604792
PMCID: PMC2997345

Complex and Multidimensional Lipid Raft Alterations in a Murine Model of Alzheimer's Disease

Abstract

Various animal models of Alzheimer's disease (AD) have been created to assist our appreciation of AD pathophysiology, as well as aid development of novel therapeutic strategies. Despite the discovery of mutated proteins that predict the development of AD, there are likely to be many other proteins also involved in this disorder. Complex physiological processes are mediated by coherent interactions of clusters of functionally related proteins. Synaptic dysfunction is one of the hallmarks of AD. Synaptic proteins are organized into multiprotein complexes in high-density membrane structures, known as lipid rafts. These microdomains enable coherent clustering of synergistic signaling proteins. We have used mass analytical techniques and multiple bioinformatic approaches to better appreciate the intricate interactions of these multifunctional proteins in the 3xTgAD murine model of AD. Our results show that there are significant alterations in numerous receptor/cell signaling proteins in cortical lipid rafts isolated from 3xTgAD mice.

1. Introduction

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders amongst adults of advanced age, and it is the most common form of dementia and cognitive impairment [1, 2]. The behavioral abnormalities in AD result from dysfunction and death of neurons in brain regions involved in cognition and mood, such as the hippocampus, amygdala, and cortical regions. Progressive short-term and eventual long-term memory loss and reduced cognitive capacity are associated with two primary neurodegenerative lesions, that is, extra- and intracellular β-amyloid plaques, as well as neurofibrillary tangles (NFTs) composed of the microtubule protein tau [35]. In addition to the effects of amyloid plaques and NFTs, the lipid trafficking molecule, apolipoprotein E4 (apoE4), has also been demonstrated to be a genetic risk factor for AD [6, 7]. The AD characteristic extracellular plaques, found in both the hippocampus and cortex of AD patients, consist of 39–42 amino acid long amyloid-β (Aβ) peptides. These extracellular peptides are generated by digestion of a transmembrane amyloid precursor protein (APP). Proteolysis of the transmembrane APP by a set of intramembrane enzymes, β- (also known as BACE-1) and γ-secretases, is thought to be responsible for toxic Aβ creation [5]. The discovery of familial mutations in the APP gene that were strongly correlated with the presentation of AD reinforced the importance of Aβ processing in this disorder. A growing body of evidence indicates that changes in lipid and cholesterol homeostasis can influence AD progression and specifically Aβ production. One of the prime sub cellular regions of amyloidogenic APP processing is thought to be cholesterol-enriched membrane microdomains, termed lipid rafts [8]. Cellular organization of protein signaling complexes, to enhance the magnitude and fidelity of transmembrane signaling receptors, is facilitated by variations in the lipid constituents of the plasma membrane. Lipid rafts represent discontinuous regions of the plasma membrane that form functional microdomains, which constrain the association of proteins in a coherent and advantageous manner with respect to neurotransmissive signaling [9]. Disruption of the correct stoichiometry of signaling complexes within lipid rafts may underpin the etiology of many different neurodegenerative disorders [1012]. The hypothesis that changes in the lipid composition of rafts contribute to AD pathology has gained considerable support. For example, ApoE4 has been strongly correlated with the generation of AD symptomatology. Both of the amyloidogenic processing enzymes (β- and γ-secretase), as well as APP, are all enriched in lipid raft membranes [13, 14]. Reinforcing the connection between lipid density levels and Aβ production, increasing cholesterol levels elevate the activity of both β-secretase (BACE-1) and γ-secretase [14, 15]. In addition, ganglioside lipids, which are also enriched in lipid rafts, can control the assembly of amyloid-β proteins [16, 17]. Changes in ganglioside composition, similar to those noted in human AD patients, are also observed in different transgenic mouse models of AD [18]. In addition to a role of the lipid components of lipid rafts in controlling amyloidogenesis, these raft environments may also affect NFTs as well. It has been demonstrated that Aβ can induce activation of the tyrosine kinase Fyn in neuronal cells, that is then recruited to lipid rafts which catalyzes phosphorylation of tyrosine residue 18 on tau [19, 20]. Association of Aβ plaques to lipid rafts can mediate recruitment of excess Fyn to the rafts, as well as further recruitment and phosphorylation of tau. These activities are thought to induce neurotoxicity via the effects of tau-induced changes in the actin cytoskeleton and receptor/cellular signaling pathways [21]. Therefore, the potential changes in the lipid composition of lipid rafts, caused by exposure to cytotoxic activities characteristic to AD, can induce profound changes in cellular signal transduction and thereby induce intracellular changes that lead to the development of AD. The complexity of protein complexes within the lipid raft environments raises considerable challenges to understanding the molecular mechanisms of AD pathophysiology in both the hippocampus and cortex of animals. Therefore, we have employed a shotgun proteomics approach, allied to advanced bioinformatic functional profiling, to gain a broad and detailed appreciation of the alterations in signaling proteins in lipid rafts in the triple-transgenic (3xTgAD) model of AD [22]. Our study demonstrates that cortical lipid rafts are profoundly affected in the 3xTgAD mice and that many of the neurophysiological deficits characteristic of AD (impaired synaptic strength, impaired learning and memory, and increased oxidative stress) can be strongly linked to changes in receptor and cell signaling events in the lipid rafts in these animals. Therefore, the lipid raft environments can be seen as one of the most important pathophysiological loci of this disorder.

2. Methods

2.1. Animals and Morris Water Maze Testing

Animal care and experimental procedures followed NIH guidelines and were approved by the National Institute on Aging Animal Care, and Use Committee. Experiments were performed using male 3xTgAD [2224] and control male C57-BL6 mice that were maintained under a 12-hour light/12-hour dark cycle with continuous access to food and water. Water maze testing took place using a modified version of the methodology described previously [25]. Briefly, animals (n = 10 per group, control male C57-BL6 or male 3xTgAD, on a C57-BL6 background) received 8 days of acquisition training using a nonvisible target platform, consisting of four trials per day, with an intertrial interval of approximately 10 minutes. Each trial lasted until the animal found the platform, or for a maximum of 60 seconds; animals that failed to find the platform within 60 seconds were guided there by the experimenter. On each trial, mice were placed into the pool, facing the wall, with start locations varied pseudorandomly. Distance swam to escape the water, escape time, and swim speed were measured for either control or 3xTgAD mice using a HVS2020 automated tracking system (HVS Image, UK).

2.2. Isolation of Lipid Raft Detergent-Resistant Membranes

The mice were anesthetized with isoflurane, decapitated, and the brain was microdissected on ice. After removal of the cortex, the tissue was split into left and right hemisphere, half for mass spectrometry raft analysis and half to prepare lipid raft tissues for Western blot analysis. The hemicortices were washed twice in ice-cold phosphate buffered saline (PBS) and then transferred into a Tris-saline buffer supplemented with a cocktail of protease and phosphatase inhibitors (50 mM Tris-HCl, 150 mM NaCl, 5 mM EDTA, and Roche Complete-Mini (Roche Diagnostics Inc.) protease and phosphatase inhibitor cocktail, pH 7.4). Crude tissue disruption was then rapidly achieved (at 4°C) using a sonic dismembrator (Fisher Scientific Model 100) followed by a brief centrifugation (4°C, 1000 ×g, 10 minutes) to pellet cell nuclei and unbroken cells. The resultant supernatant was removed and Triton X-100 (Sigma Aldrich, USA) was added to the Tris-saline buffer to a final concentration of 1%. The supernatant membranes were then incubated at 4°C for 60 minutes in the Triton X-100 Tris-saline solution. After incubation, the supernatant solution was then added to a discontinuous gradient of 30% and 60% OptiPrep (Iodixanol, Sigma Aldrich, and U.S.A.) before centrifugation at 200 000 ×g for 16 hours at 4°C. After centrifugation, a detergent-resistant lipid band was evident in the vertical solution column. Multiple fractions of 300 μl volumes were then removed from the vertical centrifugation column. Proteins were then extracted from these fractions using a proprietary ProteoExtract (EMD Biosciences) kit, according to the manufacturer's instructions. Isolated protein pellets were then prepared for mass spectrometric analysis.

2.3. Mass Spectrometric Protein Analysis

Protein pellets were dissolved into an ammonium bicarbonate buffer (100 mM, pH 8.5) and then reduced with dithiothreitol (500 mM: Pierce Biotechnology), alkylated with iodoacetamide (800 mM: Sigma Aldrich) and then digested with modified trypsin (5–10 μg) (Promega) at 37°C for 17 hours. Proteolysis was terminated by the addition of glacial acetic acid. Tryptic peptides were then loaded onto a desalting column (360 × 200 μm fused silica packed with 15 cm of C18 beads (YMC ODS-AQ, Waters)), washed with 0.1% acetic acid and eluted into sample tubes with 80% acetonitrile in 0.1% acetic acid. Sample volume was reduced to usable volumes under vacuum on a Savant SpeedVac. Samples were then transferred onto a PicoFrit (75 × 100 mm) column packed with ProteoPep II C18, 300 Å, 5 μm particles (New Objective) connected to a nanoliquid chromatography system (Dionex, Sunnyvale, CA) online with an LTQ ion trap mass spectrometer (Thermo Finnigan, San Jose, CA). The peptides were eluted using a linear gradient of 0–65% acetonitrile over 90 minutes at a flow rate of 250 nl/min directly into the mass spectrometer, which was operated to generate collision-induced dissociation spectra (data-dependent MS/MS mode). The resultant tandem mass spectrometry data were processed using the BioWorks suite, and multiple collected spectra were used to interrogate the NCBI nonredundant mouse and Swiss-Prot protein sequence databases, using the computer algorithm SEQUEST to generate accurate protein identities. Protein genpept accession identities were then converted to Official Gene Symbol terms using NIAID-DAVID v. 6.7 (http://david.abcc.ncifcrf.gov/). The statistical analysis and validation of the search results were performed using MASCOT (Matrix Science). For protein identification, a maximum of three missed tryptic cleavages was used, including fixed modification of carbamidomethylation and variable modifications of oxidized methionine and N-terminal glutamine conversion to pyroglutamic acid in the search. Only proteins with at least two validated peptides and a total score 25 and a confidence of identification of at least 95% were considered valid for reporting. Where required, additional spectral counting was performed to determine simplistic relative quantitation in conjunction with the reported number of identified unambiguous peptides per protein. Three lipid raft fraction samples (fractions 2, 3, and 4) from each three control (nontransgenic gender/age matched C57-BL6) or Alzheimer's disease (3xTgAD) were pooled and then run in an individual random order. Proteins identified based on two unambiguous peptides that were present in at least two out of the three individual animals were employed for further expression pattern analysis.

2.4. Lipid Raft Band Quantification

Digitized images of centrifugal vertical fluid columns were obtained using a Canon Digital camera and were converted from Joint Photographic Experts Group (JPG) files to a TIFF (Tagged Image File Format) form using L-Process v. 2.2 (image handling software: Fuji-Film). Image densitometry was then performed using Fuji-Film Image Gauge v. 4.2. Lipid raft band intensity was represented as a relative absorbance unit (AU) value with background (B) subtraction per square pixel (px2) (AU-B/px2).

2.5. Western Blotting Procedures

For the examination of specific proteins in cortical cell samples (both lipid raft and nonlipid raft), aliquots were removed from centrifugal fractions from Section 2.2 and their protein concentration was determined with a standard BCA protocol. Aliquot samples for western blotting analysis were then mixed with an equal volume of Laemmli sample buffer [26]. Samples were resolved using one-dimensional gel electrophoresis (SDS-PAGE), followed by electrotransfer to polyvinylenedifluoride (PVDF: PerkinElmer, Waltham, MA). PVDF membranes were blocked for one hour at room temperature in 4% nonfat milk (Santa Cruz; Santa Cruz, CA) before application of specific primary antisera in the same nonfat milk. The presence of primary antibody reactivity with the PVDF membrane was detected by the application of a 1 : 5000 dilution of a species-specific alkaline phosphatase-conjugated secondary antibody (Sigma, St. Louis, MO). PVDF-bound immune complexes of secondary and primary antibodies were subsequently detected using enzyme-linked chemifluorescence (ECF: GE Healthcare; Pittsburgh, PA). Chemifluorescent signals from the membranes were captured and quantified using a Typhoon 9410 phosphorimager (GE Healthcare, Pittsburgh, PA). Specific primary antisera used were obtained from the following sources: flotillin-1, proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), G protein-coupled receptor kinase interactor-1 (GIT-1), and paxilin antibodies were obtained from BD Bioscience, San Jose, CA; Janus kinase 2 (Jak2), v-Crk avian sarcoma virus CT10 oncogene homolog (Crk), and insulin receptor substrate-1 (IRS1) antibodies were obtained from Santa Cruz Biotechnology Corporation, CA; caspase-7, FKBP12-rapamycin complex-associated protein 1/mammalian target of rapamycin (FRAP1/mTOR), and Fyn and IGF-1 receptor beta antibodies were obtained from Cell Signaling Technology, Danvers, MA); G protein-regulated inducer of neurite outgrowth 2 (Grin2) antibody was obtained from Sigma Aldrich. For the identification of nonspecific total proteins in each sample the highly sensitive protein dye, SYPRO Ruby (Invitrogen Corporation) was employed. Fixed SDS-PAGE gels were immersed in SYPRO-Ruby for 1 hour and then washed in deionized water before scanning using a Typhoon 9410 phosphorimager (GE Healthcare, Pittsburgh, PA).

2.6. Bioinformatic Analyses

Protein identities were converted to standard gene symbol nomenclature for simplicity of usage with the batch conversion tool of NIH Bioinformatics Resources DAVID v. 6.7 (http://david.abcc.ncifcrf.gov/). Primary protein sets (containing consistently identified lipid raft extract proteins) were organized into functional signaling pathway groups and then analyzed for their differential significance of population of these canonical signaling pathways. To compare the relative degree of association of specific signaling pathways with the control or 3xTgAD protein sets, the difference between the signaling pathways “hybrid scores” was calculated (control subtracted from 3xTgAD). The magnitude of the “hybrid score” is indicative of strength and significance of association of the input protein set with the specific signaling pathway. Signaling pathway hybrid scores were generated using a process that takes into account the significant population and potential activation of that pathway by multiplying the pathway enrichment ratio (percentage of proteins in a designated pathway that were also found in the experimental dataset) and the probability (P) that the respective pathway is significantly associated with the experimental dataset. However, to create a simple numerical value, the hybrid pathway score is calculated by multiplication of the ratio with the negative log − 10 of the P value. Each signaling pathway considered was required to contain at least two unique proteins from either control or 3xTgAD datasets and possess a P value of ≤.05. Unbiased network analysis was also performed on subsets of the primary protein sets that were specifically limited to transmembrane receptor proteins. The networks generated create predictions of the most likely functional interactions between proteins in a complex dataset [27]. Networks are created to indicate the most significant series of molecular interactions. The networks with the highest predictive “scores” possess the highest number of statistically significant “focus molecules”: “focus molecules” are proteins that are present in the most statistically-likely predicted functional network and are present in the input experimental dataset. The network “score” is a numerical value used to rank networks according to their degree of relevance to the input dataset. The “score” accounts for the number of experimental focus molecules (proteins) in the network and its size, as well as the total number of proteins in the Ingenuity Knowledge Base that could potentially be included in the specific networks. The network “score” is based on the hypergeometric distribution and is calculated with the right-tailed Fisher's Exact Test. Specific scientific textual associations between filtered protein sets (transmembrane receptor proteins IPA analysis) and Alzheimer's disease processes were created using latent semantic indexing (LSI) algorithms using GeneIndexer (Computable Genomix, Incorporated: https://www.computablegenomix.com/geneindexer). GeneIndexer correlates the strength of association between specific factors (proteins) in a dataset with a user-defined interrogation term. GeneIndexer employs a 2010 murine or human database of over 1 × 106 scientific abstracts to perform text-protein correlation analysis. LSI facilitates the specific textual interrogation of an input dataset with a specific term, that is, Alzheimer's disease, to ascertain which of the input dataset proteins are explicitly associated with the interrogation term. Using LSI algorithms, not only is the direct interrogation term used to analyze the input dataset but also closely correlated additional terms, implicitly associated with the user-defined interrogation term, are also employed in the search patterns. A latent semantic indexing correlation score indicates the strength of association of the interrogation term and the specific proteins in the dataset. A highly relevant protein-term correlation yields a large number of explicitly/implicitly associated proteins with high LSI correlation scores. Therefore, a strong correlation between the proteins in a dataset and a specific user-defined interrogation term yields a large number of correlated proteins with high LSI correlation scores.

3. Statistical Analysis

Statistical analysis on multiple samples was performed using a standard nonparametric two-tailed Student's t-test using 95% confidence limits. Analyses were computed using built-in software in GraphPad Prism v. 3.0a (GraphPad Software Inc., La Jolla, CA). Results are expressed as means ± SE. P ≤ .05 was considered statistically significant. For statistical analysis using Ingenuity Pathway Analysis v. 8.5 of signaling pathways and interaction network analysis, Fisher's Exact test was employed with a P ≤ .05 cutoff. Network interaction scores were generated using a right-tailed Fisher's Exact Test.

4. Results

4.1. 3xTgAD Mice Demonstrate Impaired Learning and Memory Ability in the Morris Water Maze

Using the nonvisible Morris water maze trial and 16-month-old male control (C57-BL6) and 3xTgAD animals (n = 10 for both) we noted that the 3xTgAD mice demonstrated a significant reduction in their ability to find the location of the hidden platform (Figure 1). The 3xTgAD mice demonstrated significantly longer escape latencies and distances traveled compared to the control mice, while not showing any significant difference in calculated swim speed. Retention testing (three trials one week after the initial training) of these animals (control and 3xTgAD) also demonstrated a reduced cognitive capacity of the 3xTgAD mice compared to control (data not shown).

Figure 1
Morris Water Maze testing of control and 3xTgAD mice. (a) Distance travelled (cm) in the nonvisible probe target results for control (n = 10, blue bars) and 3xTgAD mice (n = 10, red bars) for 8 days of training. (b) Water maze escape latency (s) for days ...

4.2. 3xTgAD Mice Demonstrate a Significant Alteration in Lipid Raft Density and Protein Marker Composition

Employment of the lipid raft isolation process described in the Methods section resulted in the clear visible isolation of a detergent-resistant lipid layer comprising centrifugal fractions 2–4 (Figure 1(a)). The lipid raft marker protein, flotillin-1, was demonstrated to be specifically enriched in these centrifugal fractions (2–4) (Figure 2(a)). The visual lipid density (absorbance units-background/square pixel) of the raft layers was quantified using Fuji-Film Image Gauge. Compared to control, both 8-month-old (Figure 2(c)) and 16-month-old (Figure 2(d)) 3xTgAD-derived centrifugal raft layers demonstrated a significant (8 months old P = .027, n = 3; 16 months old P = .031, n = 3) increase in buoyant detergent-insoluble density. This 3xTgAD increase in raft size, compared to control animals, demonstrated a strong association with a significant increase in expression of flotillin-1 in the raft fractions of 3xTgAD mice, especially in centrifugal fraction 2 (Figure 2(e), P = .017, n = 3). Equal levels of total protein (measured using BCA and also SYPRO gel staining) were employed for each Western blot of the raft extracts. Quantification of fraction 2 was chosen, as this reliably indicated the greatest enrichment of this lipid raft marker. Similar quantitative alterations in expression of flotillin-1 between control and 3xTgAD mice were also seen in the additional lipid raft centrifugal fractions, that is, 3 and 4. Qualitatively similar results, with respect to 3xTgAD mouse lipid raft density and flotillin-1 expression were noted in parallel experiments carried out with age-matched female mice. In addition we also noted a similar qualitative lipid raft expression of flotillin-1 trend in male human cortex tissue (data not shown). These latter data and their significance to our current data will be further addressed in subsequent manuscripts.

Figure 2
Quantification of detergent-resistant lipid rafts. (a) The pictorial panel depicts an image of iodixanol-separated detergent resistant membrane fractions (centered on red arrow), captured using a Nikon 3200 digital camera. The line diagram indicates the ...

4.3. Differential Protein Expression in Lipid Rafts Isolated from 3xTgAD Mice Compared to Control Mice

Using an un-biased proteomic analysis of replicate lipid raft extracts, we were able to identify (from at least two individual nonambiguous peptides) multiple proteins in both control and 3xTgAD cortical extracts (control, Appendix A; 3xTgAD, Appendix B). When comparing the relative differences in lipid raft protein expression, only a small minority (17%: Figure 3(a)) of identified proteins were substantively identified in both control and 3xTgAD raft samples; however many of these common proteins identified were differentially detected (see Supplementary Table 1 in Supplementary Material available online at doi:10.4061/2010/604792). To verify the relative differential expression of multiple proteins in the control versus 3xTgAD lipid raft extracts, we also performed multiple Western blot analyses of raft centrifugal fraction-2 (F-2) samples. With loading of total equal protein quantities (50 μg: assessed in an unbiased manner with SYPRO-Ruby: Figure 3(b)) of either control or 3xTgAD F-2 samples, we assessed the relative differential expression of multiple proteins (Figures 3(c)3(n)). From the Western blot analysis it was consistently demonstrated that differential qualitative protein detection in control versus 3xTgAD raft samples strongly correlated with differential semiquantitative protein expression. Hence, the absence of consistent MS-based detection of Pyk2 (Figure 3(d)), Jak2 (Figure 3(f)), Fyn (Figure 3(h)), paxilin (Figure 3(i)), IRS-1 (Figure 3(j)), caspase 7 (Figure 3(k)), mTOR/FRAP1 (Figure 3(l)) and IGF-1R (Figure 3(n)) in control raft sample correlated to their significantly lower expression in control raft F-2 samples, compared to that in 3xTgAD samples. Conversely, the absence of consistent MS-based detection of FAK (Figure 3(c)), GIT-1 (Figure 3(e)), Crk (Figure 3(g)), and Grin2 (Figure 3(m)), correlated to their significantly lower expression in 3xTgAD raft F-2 samples, compared to that in control samples.

Figure 3
Differential protein expression in control versus 3xTgAD lipid raft extracts. (a) Proportionately drawn Venn diagram analysis of reliably identified proteins from control lipid rafts (blue line) and 3xTgAD rafts (red line). (b) Total protein loading control ...

4.4. Functional Signaling Cluster Analysis of Control versus 3xTgAD Lipid Raft Proteomes

As our MS-based multidimensional protein identification process identified several hundred proteins from each control or 3xTgAD lipid raft sample, we employed a bioinformatic analysis process to assess the relative functionalities of both the control versus 3xTgAD raft protein lists. As the majority of cellular signaling processes are mediated and regulated by multiple groups of proteins interacting with each other, we clustered, in a statistically significant manner, proteins in control or 3xTgAD animal raft samples into functional signaling groups. To assess the relative changes in regulation of classical signaling pathways, we applied a subtractive approach for the pathway “hybrid” scores (indicative of the “activity” of the specific signaling pathway: calculated by significant expression enrichment ratio of proteins in that pathway multiplied by the negative log10 (−log10) of the probability of the pathway enrichment). For each specific common signaling pathway, our mathematical approach subtracted control pathway “hybrid” scores from the pathway “hybrid” scores generated from the 3xTgAD protein set. Hence, a positive result of this subtraction indicates a greater activity of this functional pathway in 3xTgAD animals, and a negative score indicates a greater activity of this functional pathway in the control animals. Analysis of pathways involved in cellular signaling (Figure 4(a): proteins and scores in associated Appendix C) demonstrated that pathways commonly associated with cell stress responses were highly activated in 3xTgAD rafts, for example “p53 signaling”, “p38 mitogen-activated protein kinase (MAPK) signaling”, and “stress-activated protein kinase (SAPK)/JNK pathways”. In a stark contrast, prosurvival synaptic connectivity and neurotransmissive pathways were more profoundly activated in the control mice, for example, “tight junction signaling”, “calcium signaling”, “PTEN signaling”, and “Wnt/β-catenin signaling”. To investigate the specific neuronal functional effects of these disparate signaling activities, we next studied the significant clustering of raft proteins into neuron-functional pathways (Figure 4(b): Appendix D). As one would expect, the 3xTgAD mice raft protein clustering revealed a considerably greater (relative to control) activation of multiple neurodegenerative neuronal processes including: “amyloid processing”, “Amyotrophic lateral sclerosis”, “Huntington's disease signaling” and “Parkinson's signaling”. In addition to the greater activation of these degenerative processes, the 3xTgAD mice also demonstrated profound changes in the significant clustering of proteins into cytoskeletal remodeling groups (“actin cytoskeleton signaling”, regulation of actin-based motility by Rho') compared to the control mice. In accordance with our demonstration of the significant diminution of the learning and memory ability of the 3xTgAD mice, it was striking to notice the profoundly greater activation of neuron-functional pathways that control synaptic learning-dependent processes (i.e.,synaptic long-term depression”, “axonal guidance signaling”,and “synaptic long-term potentiation”) in the control mice compared to the 3xTgAD mice. Considerable evidence from multiple experimental studies has recently underlined the importance of the regulation of energy metabolism in controlling the aging process and neurodegenerative disorders [2830]. Upon inspection of the relative differences in the activation of energy-regulatory pathways created by clustering of control raft proteins versus 3xTgAD raft proteins, a profound functional distinction was noted (Figure 4(c): Appendix E). In control animals versus 3xTgAD, there was a considerably stronger activation of energy-generating pathways connected to the use of the primary metabolic substrate, that is, sugars (“amino sugars metabolism”, “glycolysis/gluconeogenesis”, and “pentose phosphate pathway”). In contrast, the energy regulatory pathways that were more strongly associated with the 3xTgAD animals involved energy derivation from alternative energy sources, for example, “synthesis and degradation of ketone bodies”, “butanoate metabolism”, and “fatty acid biosynthesis”. Many of the alterations in energy regulation in aging and degenerative disorders are thought to be associated with adaptive responses to the induction of cellular stresses, potentially through toxic effects of Aβ, NFTs and accumulated oxidative damage [30]. When the raft proteins from control and 3xTgAD mice were clustered into functional stress response pathways, again a stark contrast in the control- or 3xTgAD-associated pathways was demonstrated (Figure 4(d): Appendix F). In the 3xTgAD mice raft clustering it was noted that the association of energy-associated stressful and neuronal damage-related pathways (“PPARα/RXRα activation”, “hypoxia signaling”, “apoptosis signaling”, and “endoplasmic reticulum stress pathway”) was considerably stronger than in the control mice. Indicating a correlated connection between stress response capacity and AD pathology, there was a considerably greater association of the “Nrf2-mediated oxidative stress response pathway” in control mice compared to the 3xTgAD. Therefore, the 3xTgAD mice may demonstrate excessive neuronal stress and damage due to the attenuated activation of such stress response pathways in lipid rafts of AD synapses.

Figure 4
Functional pathway informatic clustering of control and 3xTgAD lipid raft proteins. (a) Subtractive representation of hybrid score generation after clustering of lipid raft proteins from control and 3xTgAD animal rafts into cellular signaling pathways. ...

4.5. Functional Receptor Signaling Cluster Analysis of Control versus 3xTgAD Lipid Raft Proteomes

As one of the most important functions of synaptic lipid rafts is to congregate transmembrane or juxtamembrane receptor systems [31], we next performed an in-depth investigation of the significant differential functional clustering of receptor signaling pathways between control and 3xTgAD rafts. Upon functional clustering of the raft proteins into receptor signaling pathways, strong differences in pathways association between control and 3xTgAD mice were noted (Figure 5: Appendix G). Some of the strongest differences were noted by the considerably poorer activation of growth factor-related signaling (“PDGF signaling”, “EGF signaling”, and “FGF signaling”), structural trans-synaptic receptor signaling (“Neuregulin signaling” and “Ephrin receptor signaling”), excitatory signaling (glutamate receptor signaling) and neurodevelopmental signaling (Sonic hedgehog signaling) pathways in the 3xTgAD mice, compared to the control mice. The receptor signaling profile of the 3xTgAD mice demonstrated a more profound association compared to control mice for pathways linked to inhibitory synaptic signaling (“GABA receptor signaling” and “Aryl hydrocarbon receptor signaling”: [32]), amyloid processing (“Notch signaling” and “Integrin signaling”: [33]), and neuronal stress (glucocorticoid receptor signaling). Transmembrane receptor signaling by systems including receptor tyrosine kinases or G protein-coupled receptors (GPCRs) represents one of the most important signaling mechanisms of neuronal synaptic regulation [34]. However, the activation of transmembrane receptor systems and the stimulation of their intracellular signaling cascades, especially for GPCRs, is now considered to be far more complex and intricate than initially proposed by two-state receptor models [34, 35]. Much of this additional signaling diversity is thought to arise from the additional complexity of receptor-accessory scaffolding protein modification of receptor signaling [35]. To appreciate the multiple connections between receptor (and GPCR in particular) activity and the presence of neurophysiological deficits in AD, we performed a multidimensional analysis of the proteins present in control or 3xTgAD mice. Using the novel, un-biased, bioinformatic GeneIndexer latent semantic indexing (LSI) process (https://www.computablegenomix.com/geneindexer.php), explicit correlations can be made between protein/gene factors from input datasets and their linkage (in over 1 × 106 curated scientific abstracts) to a specific interrogation term, for example, Alzheimer's. The semantic indexing algorithms of GeneIndexer also allow for multidimensional correlations to be measured for terms significantly related to the interrogation term, hence providing a flexible, intelligent query process. For the control and 3xTgAD datasets, we employed multiple interrogation terms targeted to demonstrate differences between control and 3xTgAD datasets. Using the following interrogation terms: Alzheimer's, oxidation, neurodegeneration, synaptic transmission, neurogenesis, scaffolding, and GPCR, we demonstrated that, at a multidimensional interactive level, there is minimal functional cross-over between control and 3xTgAD raft samples (Figure 6: Appendix H). Only proteins that demonstrated explicit correlations (latent semantic indexing score of ≥0.1) to at least two of the interrogation terms are denoted in the multidimensional heatmap (Figure 6: Appendix H). Therefore, each of the proteins identified in the heatmap are strongly correlated with many of the connected interrogation terms and therefore show potential synergistic activity. Analysis of identified proteins in this manner, that is, selected specifically for multidimensional neurological roles, allows for an un-biased focusing on proteins that may possess keystone-like functions in the molecular signaling networks involved in neurodegeneration. With respect to specific interrogation terms, a strong validation of the technique is demonstrated by the fact that using the Alzheimer's interrogation term, 47 3xTgAD-unique multidimensional proteins were indicated while only 10 such multidimensional proteins were shown in control rafts (Figure 6). Confirming a strong role of oxidative damage, 21 3xTgAD-unique multidimensional proteins were present in the oxidation results while only 6 such control-unique were demonstrated. Interestingly and perhaps suggestive of a potential future line of AD research was the observation that considerably fewer multidimensional 3xTgAD-unique proteins were associated with the process of neurogenesis (15), compared to the 32 control-unique multidimensional proteins associated with this neuroprotective mechanism. In accordance with the important role of receptor systems in AD, we additionally noted that more 3xTgAD-unique proteins were associated with GPCRs (27) compared to control-unique GPCR-related multidimensional proteins (16).

Figure 5
Functional receptor signaling pathway informatic clustering of control and 3xTgAD lipid raft proteins. Subtractive representation of hybrid score generation after clustering of raft proteins from control and 3xTgAD animal rafts into receptor signaling ...
Figure 6
Multidimensional protein latent semantic indexing (LSI) analysis of proteins extracted from control and 3xTgAD lipid rafts. Proteins from the control or 3xTgAD extracted datasets that possessed an explicit latent semantic indexing (LSI, GeneIndexer, Computable ...

4.6. Functional Interaction Networks of Receptor Signaling Proteins in Control versus 3xTgAD Lipid Raft Proteomes

From our investigation of the multidimensional nature of raft proteins with respect to neurodegenerative processes, it is clear that there are many factors that are highly likely to work together in complex and intricate functional networks. To investigate the nature of the most statistically likely functional network interactions, we employed IPA network analysis of a receptor-filtered (using IPA-knowledge base data filtering, IPA v. 8,5) subset of the control or 3xTgAD raft protein datasets (Tables (Tables11 and and2,2, resp.). Using these datasets, un-biased network analysis is able to predict the most likely series of functional interactions (based on empirically derived experimental evidence) that take place between the receptor-associated raft proteins. The control and 3xTgAD receptor-specific filtered datasets demonstrated a relatively minimal overlap, that is, 11.6% commonality, indicating that substantial alterations of these proteins may occur in the rafts of 3xTgAD animals (Figure 7(a)). The most statistically likely interaction network that was predicted to occur in control mice centered on neuroprotective and neurotransmissive factors such as phosphoinositide-3-kinse (PI3K), Akt-1, muscarinic GPCRs (Chrm5), and glutamate receptors (Grm5) (Figure 7(a): Appendix I). In contrast, the highest statistically scoring network from 3xTgAD receptor-specific proteins was centered on lipid-regulating factors and stress-related factors including: p38 MAPK; Jnk (c-jun N-terminal kinase), Lrpap1 (low-density lipoprotein receptor-related protein associated protein 1); LDL (low density lipoprotein), and NF-κB (Figure 7(b): Appendix J). Therefore, at the level of functional interaction of receptor-related proteins in the lipid rafts, it is clear that these membrane microdomains are a strong functional locus of this degenerative disease. Reinforcing this AD-relevant microcosm effect in the lipid rafts we analyzed, using latent semantic indexing (LSI) interrogation of these receptor-specific datasets (Table 2—control; Appendix I-3xTgAD), the Alzheimer's disease correlation of these receptor-specific proteins. In Figure 8, we demonstrate that almost twice as many proteins in the 3xTgAD dataset (21) explicitly correlated with the interrogation term Alzheimer's disease compared to the proteins in the control dataset (11). The degree of correlation of the interrogation term (Alzheimer's) to each specific protein is indicated by the LSI score. In Figure 8(b) the cumulated LSI score for the 3xTgAD Alzheimer's-related proteins was 2.92 while for the control proteins only 1.21 (Figure 8(b)), demonstrating that a much stronger correlation of receptor-associated proteins existed for the proteins in 3xTgAD rafts, compared to control. Upon comparison of the phylogenetic relationships of the receptor-specific proteins that form the most likely functional networks (from Figure 7(b)), it is clear that for the control-set proteins only three of these in this network are highly correlated to reports of Alzheimer's disease (27.2%: Figure 8(c)) while the most coherent interaction network of 3xTgAD raft proteins possessed a much higher percentage of Alzheimer's disease-related proteins (62%: Figure 8(d)). Therefore, this suggests that one of the important pathological loci of AD could be the disruption of interactivity of receptor-associated proteins in the lipid raft microdomains and that such a finding can be uncovered in a completely un-biased informatic format from extremely large and difficult to interpret datasets.

Figure 7
Receptor-restricted control and 3xTgAD network interaction analysis. (a) Proportionally drawn Venn diagram depicting the relative distribution between control or 3xTgAD raft samples of receptor-specific proteins filtered using IPA version 8.5 (control ...
Figure 8
Alzheimer's disease correlation of control or 3xTgAD receptor-specific lipid raft proteins. (a) The histogram represents the number of receptor-specific raft proteins (Table 1: control, Table 2: 3xTgAD) that demonstrate an explicit LSI correlation to ...
Table 1
Receptor-specific protein list from lipid raft extracts from control animals. Primary protein lists of extracted lipid raft proteins were filtered for a specific receptor profile using IPA v. 8.5.
Table 2
Receptor-specific protein list from lipid raft extracts from 3xTgAD animals. Primary protein lists of extracted lipid raft proteins were filtered for a specific receptor profile using IPA v. 8.5.

5. Discussion

Multiple informatic techniques were employed to investigate and elucidate the nature of functional protein interactions that occur differentially in the lipid raft microdomains of control versus 3xTgAD Alzheimer's disease mice. Cognitively impaired male 3xTgAD mice showed profound differences in the protein constituents of lipid raft extracts compared to age-matched control mice, that is, only 17% of raft proteins were similar between the two groups of mice. Our microdomain proteomic approach was able to specifically assist in the identification of altered proteins that are highly characteristic of AD-related raft pathophysiology, for example, the Src-family tyrosine kinase Fyn (Figure 3(h)) [19, 20].

Currently, biological scientists are often faced with complex biological issues concerning the interpretation of their results due to the development of facile mass data acquisition technologies, that is, extracting relevant and illuminating information from large datasets is often extremely challenging. However, with the application of multiple, sequential un-biased informatic processes, we were able to identify specific lipid raft involvement in altered pathways that can control multiple degenerative mechanisms, for example, attenuation of the Wnt/β-catenin signaling pathway, profound reduction of the important Nrf2 stress response pathway (Figure 4(d)), the loss of neurogenesis association, and the important involvement of synaptic GPCR-systems (Figure 6) in the 3xTgAD mice [3638].

Elucidation of the crucial signaling relationships in this degenerative disorder, and the identity of the proteins that mediate them, could lead to the more rational development of novel therapeutics for Alzheimer's disease. Using our informatic receptor-targeted approach, we were also able to reinforce the validity of our discovery process by also identifying the importance of energy-related insulin/insulin-like growth factor (IGF) signaling in AD (Figures 3(j), 3(n), ,5,5, and 8(d)) that has recently become more widely appreciated by other researchers [3942]. In addition to IGF receptor activity, we noted a potential implication of the presynaptic latrophilins (lphn) in AD pathophysiology (Figure 8(d)). These unique receptors form the high affinity target of α-latrotoxin and may be able to integrate presynaptic calcium regulation with an ability to potentially physically interact with the postsynaptic neuron [43]. Another receptor signaling system that our analysis revealed to possess a potential role in AD is the Sonic Hedgehog (Shh) systems (Figures (Figures55 and 8(d)). With a specific correlation to AD pathophysiology, it has been demonstrated that Shh can act in a synergistic manner with nerve growth factor to act on central nervous system cholinergic neurons [44], and cholinergic insufficiency has been strongly associated with cognitive decline and Alzheimer's-related pathophysiology [45].

6. Conclusions

The combined use of broad range proteomic analysis, with sequential multidimensional informatic analysis enables the determination of important correlations between pathophysiology and functional protein differences. Using discrete proteomes, that is, lipid raft extracts, versus whole-cell/tissue proteomes, facilitates an improved ability to understand the complex interactivity between transmembrane receptor protein systems in a disease setting. The appreciation and clustering of protein datasets into coherent groups greatly increases our capacity to focus upon potentially important therapeutic target networks. The knowledge gained of protein activity networks may greatly assist in the future development of network-targeting therapeutics that possess a multidimensional efficacy at several interacting proteins.

Supplementary Material

Supplementary Table 1: the table illustrates the top 50 most upregulated and top 50 most downregulated (italics) proteins (commonly identified in 3xTgAD and control WT) in 3xTgAD cortical raft extracts compared to WT.

Ranking was based on relative expression ratios generated by spectral counting for 3xTgAD:WT proteins that displayed a >95% identity confidence.

Proteins ranked 1-50 for 3xTgAD>WT (increased in 3xTgAD compared to WT) represent those with expression ratios (3xTgAD:WT) greater than unity while proteins ranked 1-50 for WT>3xTgAD (decreased in 3xTgAD compared to WT: italics) represents those with expression ratios (3xTgAD:WT) less than unity. In each case the most up or downregulated proteins are ranked 1.

Acknowledgments

This work was carried out with the support of the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The authors thank Dr. LaFerla for kindly donating 3xTgAD breeding pairs to the National Institute on Aging.

Appendices

A.

Lipid raft-derived extracted proteins from control mouse 16-month-old cortical tissue. Specific proteins isolated from control mouse cortex were identified with multidimensional protein identification technology (MudPIT) LC MS/MS. Each protein was identified in at least two out of three experimental replicate animals and from at least two isolated peptides per protein. The following are the protein symbol and its corresponding definitions.

  • Atm: ataxia telangiectasia mutated
  • Bcat1: branched chain aminotransferase 1, cytosolic
  • Bcl11a: B-cell CLL/lymphoma 11A (zinc finger protein)
  • Bnip1: BCL2/adenovirus E1B 19 kDa interacting protein 1
  • Brd2: bromodomain containing 2
  • Bteb1: Kruppel-like factor 9
  • Bzrap1: benzodiazepine receptor (peripheral) associated protein 1
  • C3: complement component 3
  • C5: complement component 5
  • Cacna1a: calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
  • Cacna1c: calcium channel, voltage-dependent, L type, alpha 1C subunit
  • Cacna2d2: calcium channel, voltage-dependent, alpha 2/delta subunit 2
  • Cadps: Ca++-dependent secretion activator
  • Calb1: calbindin 1, 28 kDa
  • Calb2: calbindin 2
  • Calm2: calmodulin 2 (phosphorylase kinase, delta)
  • Camkk1: calcium/calmodulin-dependent protein kinase kinase 1, alpha
  • Camkk2: calcium/calmodulin-dependent protein kinase kinase 2, beta
  • Cap1: CAP, adenylate cyclase-associated protein 1 (yeast)
  • Cast: calpastatin
  • Cat: catalase
  • Catsper2: cation channel, sperm associated 2
  • Cav1: caveolin 1, caveolae protein, 22 kDa
  • Cblb: Cas-Br-M (murine) ecotropic retroviral transforming sequence b
  • Cbp: opsin 1 (cone pigments), long-wave-sensitive
  • Cbr1: carbonyl reductase 1
  • Cbwd1: COBW domain containing 1
  • Cbx5: chromobox homolog 5 (HP1 alpha homolog, Drosophila)
  • Ccbl1: cysteine conjugate-beta lyase, cytoplasmic
  • Ccin: calicin
  • Ccl28: chemokine (C-C motif) ligand 28
  • Ccl4: chemokine (C-C motif) ligand 4
  • ccnb1: cyclin B1
  • Ccnc: cyclin C
  • Cct2: chaperonin containing TCP1, subunit 2 (beta)
  • Cct3: chaperonin containing TCP1, subunit 3 (gamma)
  • Cct4: chaperonin containing TCP1, subunit 4 (delta)
  • Cct5: chaperonin containing TCP1, subunit 5 (epsilon)
  • Cct6a: chaperonin containing TCP1, subunit 6A (zeta 1)
  • Cd1: ribosomal protein L5
  • Cd151: CD151 molecule (Raph blood group)
  • Cd200: CD200 molecule
  • Cd276: CD276 molecule
  • Cd2ap: CD2-associated protein
  • Cd4: CD4 molecule
  • Cdc10: septin 7
  • Cdc25b: cell division cycle 25 homolog B (S. pombe)
  • Cdc42: cell division cycle 42 (GTP binding protein, 25 kDa)
  • Cdc42bpa: CDC42 binding protein kinase alpha (DMPK-like)
  • Cdc5l: CDC5 cell division cycle 5-like (S. pombe)
  • Cdh1: cadherin 1, type 1, E-cadherin (epithelial)
  • Cdh10: cadherin 10, type 2 (T2-cadherin)
  • Cdh2: cadherin 2, type 1, N-cadherin (neuronal)
  • Cdh4: cadherin 4, type 1, R-cadherin (retinal)
  • Cdk2: cyclin-dependent kinase 2
  • Cdk5rap2: CDK5 regulatory subunit associated protein 2
  • Cdk5rap3: CDK5 regulatory subunit associated protein 3
  • Cdk6: cyclin-dependent kinase 6
  • Cdk7: cyclin-dependent kinase 7
  • Cdkl2: cyclin-dependent kinase-like 2 (CDC2-related kinase)
  • Cdkl3: cyclin-dependent kinase-like 3
  • Cdkn1b: cyclin-dependent kinase inhibitor 1B (p27, Kip1)
  • Cds1: CDP-diacylglycerol synthase (phosphatidate cytidylyltransferase) 1
  • Cdv1: intraflagellar transport 81 homolog (Chlamydomonas)
  • Cebpe: CCAAT/enhancer binding protein (C/EBP), epsilon
  • Cebpz: CCAAT/enhancer binding protein (C/EBP), zeta
  • Celsr2: cadherin, EGF LAG seven-pass G-type receptor 2 (flamingo homolog, Drosophila)
  • Celsr3: cadherin, EGF LAG seven-pass G-type receptor 3 (flamingo homolog, Drosophila)
  • Cend1: cell cycle exit and neuronal differentiation 1
  • Cenpf: centromere protein F, 350/400ka (mitosin)
  • Centa1: ArfGAP with dual PH domains 1
  • Centg1: ArfGAP with GTPase domain, ankyrin repeat and PH domain 2
  • Cep350: centrosomal protein 350 kDa
  • Ces1: carboxylesterase 1 (monocyte/macrophage serine esterase 1)
  • Ces3: carboxylesterase 3
  • Cetn2: centrin, EF-hand protein, 2
  • Cetn3: centrin, EF-hand protein, 3 (CDC31 homolog, yeast)
  • Cfh: complement factor H
  • Cfl1: cofilin 1 (nonmuscle)
  • Chd3: chromodomain helicase DNA binding protein 3
  • Chd4: chromodomain helicase DNA binding protein 4
  • Chga: chromogranin A (parathyroid secretory protein 1)
  • Chl1: cell adhesion molecule with homology to L1CAM (close homolog of L1)
  • Chmp1a: chromatin modifying protein 1A
  • Chn2: chimerin (chimaerin) 2
  • Chrm5: cholinergic receptor, muscarinic 5
  • Chrnb3: cholinergic receptor, nicotinic, beta 3
  • Chrnb4: cholinergic receptor, nicotinic, beta 4
  • Chrng: cholinergic receptor, nicotinic, gamma
  • Chst7: carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7
  • Chx10: visual system homeobox 2
  • Cirbp: cold inducible RNA binding protein
  • Cit: citron (rho-interacting, serine/threonine kinase 21)
  • Cktsf1b1: gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
  • Clasp2: cytoplasmic linker associated protein 2
  • Clcc1: chloride channel CLIC-like 1
  • Clcn7: chloride channel 7
  • Cldn1: claudin 1
  • Cldn19: claudin 19
  • Cldn4: claudin 4
  • CLEC10A: C-type lectin domain family 10, member A
  • Clecsf6: C-type lectin domain family 4, member A
  • Clic4: chloride intracellular channel 4
  • CLIP3: CAP-GLY domain containing linker protein 3
  • Clpb: ClpB caseinolytic peptidase B homolog (E. coli)
  • Clstn1: calsyntenin 1
  • Cltb: clathrin, light chain (Lcb)
  • Cndp2: CNDP dipeptidase 2 (metallopeptidase M20 family)
  • Cnga1: cyclic nucleotide gated channel alpha 1
  • Cnga4: cyclic nucleotide gated channel alpha 4
  • Cnksr2: connector enhancer of kinase suppressor of Ras 2
  • Cnot6: CCR4-NOT transcription complex, subunit 6
  • Cnp: 2',3'-cyclic nucleotide 3' phosphodiesterase
  • Cnr1: cannabinoid receptor 1 (brain)
  • Cntfr: ciliary neurotrophic factor receptor
  • Cntn1: contactin 1
  • Cog3: component of oligomeric golgi complex 3
  • Colm: gliomedin
  • Copa: coatomer protein complex, subunit alpha
  • Copb1: coatomer protein complex, subunit beta 1
  • COPB2: coatomer protein complex, subunit beta 2 (beta prime)
  • Cops4: COP9 constitutive photomorphogenic homolog subunit 4 (Arabidopsis)
  • Cops8: COP9 constitutive photomorphogenic homolog subunit 8 (Arabidopsis)
  • Coro1a: coronin, actin binding protein, 1A
  • Coro7: coronin 7
  • Cp: ceruloplasmin (ferroxidase)
  • Cpe: carboxypeptidase E
  • Cplx1: complexin 1
  • Cpt1a: carnitine palmitoyltransferase 1A (liver)
  • Cpt2: carnitine palmitoyltransferase 2
  • Crabp2: cellular retinoic acid binding protein 2
  • Crhbp: corticotropin releasing hormone binding protein
  • Crip2: cysteine-rich protein 2
  • Crk: v-crk sarcoma virus CT10 oncogene homolog (avian)
  • Crkl: v-crk sarcoma virus CT10 oncogene homolog (avian)-like
  • Crmp1: collapsin response mediator protein 1
  • Crnkl1: crooked neck pre-mRNA splicing factor-like 1 (Drosophila)
  • Crp: C-reactive protein, pentraxin-related
  • Cry1: cryptochrome 1 (photolyase-like)
  • Crygc: crystallin, gamma C
  • Crygs: crystallin, gamma S
  • Crym: crystallin, mu
  • Cs: citrate synthase
  • Csf1: colony stimulating factor 1 (macrophage)
  • Csnk1e: casein kinase 1, epsilon
  • Csnk1g2: casein kinase 1, gamma 2
  • Csnk2a1: casein kinase 2, alpha 1 polypeptide
  • Csnk2b: casein kinase 2, beta polypeptide
  • Cspg2: versican
  • Cspg3: neurocan
  • Cspg5: chondroitin sulfate proteoglycan 5 (neuroglycan C)
  • Cspg6: structural maintenance of chromosomes 3
  • Cst6: cystatin E/M
  • Cstb: cystatin B (stefin B)
  • Ctf1: cardiotrophin 1
  • Cthrc1: collagen triple helix repeat containing 1
  • Ctla4: cytotoxic T-lymphocyte-associated protein 4
  • Ctnnb1: catenin (cadherin-associated protein), beta 1, 88 kDa
  • Ctnnd2: catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein)
  • Ctrb: chymotrypsinogen B1
  • Ctrl: chymotrypsin-like
  • Ctsd: cathepsin D
  • Cttn: cortactin
  • Cttnbp2: cortactin binding protein 2
  • Cul1: cullin 1
  • Cul5: cullin 5
  • Cuta: cutA divalent cation tolerance homolog (E. coli)
  • Cutl1: cut-like homeobox 1
  • CX3CL1: chemokine (C-X3-C motif) ligand 1
  • Cxadr: coxsackie virus and adenovirus receptor
  • Cxcl2: chemokine (C-X-C motif) ligand 2
  • Cyb5: cytochrome b5 type A (microsomal)
  • Cyb5b: cytochrome b5 type B (outer mitochondrial membrane)
  • Cyb5r1: cytochrome b5 reductase 1
  • Cybb: cytochrome b-245, beta polypeptide
  • Cyln2: CAP-GLY domain containing linker protein 2
  • Cyp2s1: cytochrome P450, family 2, subfamily S, polypeptide 1
  • Cyr61: cysteine-rich, angiogenic inducer, 61
  • Dab2: disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila)
  • Dab2ip: DAB2 interacting protein
  • Dad1: defender against cell death 1
  • Dag1: dystroglycan 1 (dystrophin-associated glycoprotein 1)
  • Dap: death-associated protein
  • Dapk3: death-associated protein kinase 3
  • Dbc1: deleted in bladder cancer 1
  • DBH: dopamine beta-hydroxylase (dopamine beta-monooxygenase)
  • Dbn1: drebrin 1
  • Dbndd2: dysbindin (dystrobrevin binding protein 1) domain containing 2
  • Dbnl: drebrin-like
  • Dcd: dermcidin
  • Dci: dodecenoyl-Coenzyme A delta isomerase (3,2 trans-enoyl-Coenzyme A isomerase)
  • Dclk2: doublecortin-like kinase 2
  • Dclre1c: DNA cross-link repair 1C (PSO2 homolog, S. cerevisiae)
  • Dctn2: dynactin 2 (p50)
  • Ddah2: dimethylarginine dimethylaminohydrolase 2
  • Ddb1: damage-specific DNA binding protein 1, 127 kDa
  • Ddn: dendrin
  • Ddost: dolichyl-diphosphooligosaccharide-protein glycosyltransferase
  • Ddr2: discoidin domain receptor tyrosine kinase 2
  • Ddt: D-dopachrome tautomerase
  • Ddx1: DEAD (Asp-Glu-Ala-Asp) box polypeptide 1
  • Ddx17: DEAD (Asp-Glu-Ala-Asp) box polypeptide 17
  • Ddx47: DEAD (Asp-Glu-Ala-Asp) box polypeptide 47
  • Ddx5: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5
  • Decr1: 2,4-dienoyl CoA reductase 1, mitochondrial
  • Des: desmin
  • Dgcr14: DiGeorge syndrome critical region gene 14
  • Dgkb: diacylglycerol kinase, beta 90 kDa
  • Dgkg: diacylglycerol kinase, gamma 90 kDa
  • Dhcr7: 7-dehydrocholesterol reductase
  • Dhodh: dihydroorotate dehydrogenase
  • Dhrs8: hydroxysteroid (17-beta) dehydrogenase 11
  • Dhx16: DEAH (Asp-Glu-Ala-His) box polypeptide 16
  • Dhx30: DEAH (Asp-Glu-Ala-His) box polypeptide 30
  • Dia1: cytochrome b5 reductase 3
  • Dio1: deiodinase, iodothyronine, type I
  • Disc1: disrupted in schizophrenia 1
  • Dkc1: dyskeratosis congenita 1, dyskerin
  • Dlat: dihydrolipoamide S-acetyltransferase
  • Dlc1: deleted in liver cancer 1
  • Dld: dihydrolipoamide dehydrogenase
  • Dlgap1: discs, large (Drosophila) homolog-associated protein 1
  • Dlgap2: discs, large (Drosophila) homolog-associated protein 2
  • Dlgap4: discs, large (Drosophila) homolog-associated protein 4
  • Dll1: delta-like 1 (Drosophila)
  • Dll3: delta-like 3 (Drosophila)
  • Dlx5: distal-less homeobox 5
  • Dmd: dystrophin
  • Dmn: synemin, intermediate filament protein
  • Dmrt1: doublesex and mab-3 related transcription factor 1
  • Dnah6: dynein, axonemal, heavy chain 6
  • Dnaja2: DnaJ (Hsp40) homolog, subfamily A, member 2
  • Dnch1: dynein, cytoplasmic 1, heavy chain 1
  • Dncl2a: dynein, light chain, roadblock-type 1
  • Dntt: deoxynucleotidyltransferase, terminal
  • Dock9: dedicator of cytokinesis 9
  • Dpp3: dipeptidyl-peptidase 3
  • Dpyd: dihydropyrimidine dehydrogenase
  • Dpysl3: dihydropyrimidinase-like 3
  • Dpysl4: dihydropyrimidinase-like 4
  • Drd1ip: calcyon neuron-specific vesicular protein
  • Drg1: developmentally regulated GTP binding protein 1
  • Drpla: atrophin 1
  • Dscam: Down syndrome cell adhesion molecule
  • Dscr1l1: regulator of calcineurin 2
  • Dtnb: dystrobrevin, beta
  • Duox1: dual oxidase 1
  • Dusp12: dual specificity phosphatase 12
  • Dusp2: dual specificity phosphatase 2
  • Dvl1: dishevelled, dsh homolog 1 (Drosophila)
  • Dync1h1: dynein, cytoplasmic 1, heavy chain 1
  • Dync1li2: dynein, cytoplasmic 1, light intermediate chain 2
  • Dyx1c1: dyslexia susceptibility 1 candidate 1
  • Eaf2: ELL associated factor 2
  • Ecel1: endothelin converting enzyme-like 1
  • Echdc1: enoyl Coenzyme A hydratase domain containing 1
  • Ecm1: extracellular matrix protein 1
  • Ecm2: extracellular matrix protein 2, female organ and adipocyte specific
  • Edf1: endothelial differentiation-related factor 1
  • Ednrb: endothelin receptor type B
  • Eef2: eukaryotic translation elongation factor 2
  • Efcbp1: N-terminal EF-hand calcium binding protein 1
  • Efemp2: EGF-containing fibulin-like extracellular matrix protein 2
  • Efnb1: ephrin-B1
  • Egf: epidermal growth factor (beta-urogastrone)
  • Egfl3: multiple EGF-like-domains 6
  • Egfr: epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)
  • Ehd2: EH-domain containing 2
  • Ehd4: EH-domain containing 4
  • Eif2c2: eukaryotic translation initiation factor 2C, 2
  • Eif5b: eukaryotic translation initiation factor 5B
  • Elac2: elaC homolog 2 (E. coli)
  • Elavl3: ELAV (embryonic lethal, abnormal vision, Drosophila)-like 3 (Hu antigen C)
  • ELK1: ELK1, member of ETS oncogene family
  • Elmo1: engulfment and cell motility 1
  • Emb: embigin homolog (mouse)
  • Emd: emerin
  • Eml5: echinoderm microtubule associated protein like 5
  • Enah: enabled homolog (Drosophila)
  • Enc1: ectodermal-neural cortex (with BTB-like domain)
  • Eno2: enolase 2 (gamma, neuronal)
  • Eno3: enolase 3 (beta, muscle)
  • Enpp2: ectonucleotide pyrophosphatase/phosphodiesterase 2
  • Enpp3: ectonucleotide pyrophosphatase/phosphodiesterase 3
  • Enpp5: ectonucleotide pyrophosphatase/phosphodiesterase 5 (putative function)
  • Ensa: endosulfine alpha
  • Entpd2: ectonucleoside triphosphate diphosphohydrolase 2
  • Entpd8: ectonucleoside triphosphate diphosphohydrolase 8
  • Epha3: EPH receptor A3
  • Epha5: EPH receptor A5
  • Epha7: EPH receptor A7
  • Ephb3: EPH receptor B3
  • Ephx1: epoxide hydrolase 1, microsomal (xenobiotic)
  • Epn1: epsin 1
  • Eprs: glutamyl-prolyl-tRNA synthetase
  • Eps8l1: EPS8-like 1
  • Erap1: endoplasmic reticulum aminopeptidase 1
  • Erbb3: v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)
  • Erbb4: v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)
  • Ercc5: excision repair cross-complementing rodent repair deficiency, complementation group 5
  • Erp29: endoplasmic reticulum protein 29
  • Esd: esterase D/formylglutathione hydrolase
  • Esr2: estrogen receptor 2 (ER beta)
  • Etfb: electron-transfer-flavoprotein, beta polypeptide
  • Ets1: v-ets erythroblastosis virus E26 oncogene homolog 1 (avian)
  • Evl: Enah/Vasp-like
  • Exoc5: exocyst complex component 5
  • Exoc7: exocyst complex component 7
  • Ezr: ezrin
  • Fabp1: fatty acid binding protein 1, liver
  • Fabp2: fatty acid binding protein 2, intestinal
  • Fabp3: fatty acid binding protein 3, muscle and heart (mammary-derived growth inhibitor)
  • Fabp4: fatty acid binding protein 4, adipocyte
  • Fabp7: fatty acid binding protein 7, brain
  • Fads1: fatty acid desaturase 1
  • Fads2: fatty acid desaturase 2
  • Faim: Fas apoptotic inhibitory molecule
  • Fancd2: Fanconi anemia, complementation group D2
  • Faslg: Fas ligand (TNF superfamily, member 6)
  • Fasn: fatty acid synthase
  • Fat: FAT tumor suppressor homolog 1 (Drosophila)
  • Fat3: FAT tumor suppressor homolog 3 (Drosophila)
  • Fbn1: fibrillin 1
  • Fbn2: fibrillin 2
  • Fbxw11: F-box and WD repeat domain containing 11
  • Fetub: fetuin B
  • FGA: fibrinogen alpha chain
  • Fgb: fibrinogen beta chain
  • Fgf18: fibroblast growth factor 18
  • Fgf23: fibroblast growth factor 23
  • Fgfr1: fibroblast growth factor receptor 1
  • Fgfr1op2: FGFR1 oncogene partner 2
  • Fgfr2: fibroblast growth factor receptor 2
  • Fgfr3: fibroblast growth factor receptor 3
  • Fhl1: four and a half LIM domains 1
  • Fignl1: fidgetin-like 1
  • Fip1l1: FIP1 like 1 (S. cerevisiae)
  • Fkbp14: FK506 binding protein 14, 22 kDa
  • Fkbp1b: FK506 binding protein 1B, 12.6 kDa
  • Fkbp5: FK506 binding protein 5
  • Flg: filaggrin
  • Flii: flightless I homolog (Drosophila)
  • Fmo3: flavin containing monooxygenase 3
  • Fnta: farnesyltransferase, CAAX box, alpha
  • Fos: FBJ murine osteosarcoma viral oncogene homolog
  • Fpgt: fucose-1-phosphate guanylyltransferase
  • Freq: frequenin homolog (Drosophila)
  • Fshr: follicle stimulating hormone receptor
  • Fthfd: aldehyde dehydrogenase 1 family, member L1
  • Fuca1: fucosidase, alpha-L-1, tissue
  • fut10: fucosyltransferase 10 (alpha (1,3) fucosyltransferase)
  • Fxc1: fracture callus 1 homolog (rat)
  • Fxyd6: FXYD domain containing ion transport regulator 6
  • Fzd9: frizzled homolog 9 (Drosophila)
  • Gaa: glucosidase, alpha; acid
  • Gabarap: GABA(A) receptor-associated protein
  • Gabarapl2: GABA(A) receptor-associated protein-like 2
  • Gabbr1: gamma-aminobutyric acid (GABA) B receptor, 1
  • Gabra3: gamma-aminobutyric acid (GABA) A receptor, alpha 3
  • Gabrg2: gamma-aminobutyric acid (GABA) A receptor, gamma 2
  • Gabrr3: gamma-aminobutyric acid (GABA) receptor, rho 3
  • Gadd45a: growth arrest and DNA-damage-inducible, alpha
  • Galc: galactosylceramidase
  • Galk1: galactokinase 1
  • Galt: galactose-1-phosphate uridylyltransferase
  • Gapdh: glyceraldehyde-3-phosphate dehydrogenase
  • Gars: glycyl-tRNA synthetase
  • Gas6: growth arrest-specific 6
  • Gas7: growth arrest-specific 7
  • Gata2: GATA binding protein 2
  • Gata3: GATA binding protein 3
  • GC: group-specific component (vitamin D binding protein)
  • Gc: group-specific component (vitamin D binding protein)
  • Gcgr: glucagon receptor
  • Gckr: glucokinase (hexokinase 4) regulator
  • Gclc: glutamate-cysteine ligase, catalytic subunit
  • Gcnt3: glucosaminyl (N-acetyl) transferase 3, mucin type
  • Gdap2: ganglioside induced differentiation associated protein 2
  • Gdi1: GDP dissociation inhibitor 1
  • Gdi2: GDP dissociation inhibitor 2
  • Gfap: glial fibrillary acidic protein
  • Gfpt2: glutamine-fructose-6-phosphate transaminase 2
  • Gfra1: GDNF family receptor alpha 1
  • Gfra3: GDNF family receptor alpha 3
  • Ggt1: gamma-glutamyltransferase 1
  • Ggtl3: gamma-glutamyltransferase 7
  • Ggtla1: gamma-glutamyltransferase 5
  • Ghitm: growth hormone inducible transmembrane protein
  • Gif: gastric intrinsic factor (vitamin B synthesis)
  • Gipc1: GIPC PDZ domain containing family, member 1
  • Git1: G protein-coupled receptor kinase interacting ArfGAP 1
  • Gja1: gap junction protein, alpha 1, 43 kDa
  • Gja10: gap junction protein, alpha 10, 62 kDa
  • Gja4: gap junction protein, alpha 4, 37 kDa
  • Gjb6: gap junction protein, beta 6, 30 kDa
  • Gla: galactosidase, alpha
  • Gldc: glycine dehydrogenase (decarboxylating)
  • Glg1: golgi apparatus protein 1
  • Gli: GLI family zinc finger 1
  • Glo1: glyoxalase I
  • Glra2: glycine receptor, alpha 2
  • Glrx2: glutaredoxin 2
  • Glud1: glutamate dehydrogenase 1
  • Glul: glutamate-ammonia ligase (glutamine synthetase)
  • Gm2a: GM2 ganglioside activator
  • Gmcl1: germ cell-less homolog 1 (Drosophila)
  • Gmfb: glia maturation factor, beta
  • Gmfg: glia maturation factor, gamma
  • Gmpr2: guanosine monophosphate reductase 2
  • Gng7: guanine nucleotide binding protein (G protein), gamma 7
  • Gnpat: glyceronephosphate O-acyltransferase
  • Gns: glucosamine (N-acetyl)-6-sulfatase
  • Golga2: golgi autoantigen, golgin subfamily a, 2
  • Golgb1: golgin B1, golgi integral membrane protein
  • Golph3: golgi phosphoprotein 3 (coat-protein)
  • Golph4: golgi integral membrane protein 4
  • Gosr2: golgi SNAP receptor complex member 2
  • Got1: glutamic-oxaloacetic transaminase 1, soluble (aspartate aminotransferase 1)
  • Got2: glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)
  • Gpam: glycerol-3-phosphate acyltransferase, mitochondrial
  • Gpc2: glypican 2
  • Gpi: glucose phosphate isomerase
  • Gpm6a: glycoprotein M6A
  • Gpr116: G protein-coupled receptor 116
  • Gpr141: G protein-coupled receptor 141
  • Gprc6a: G protein-coupled receptor, family C, group 6, member A
  • Gpsm1: G-protein signaling modulator 1 (AGS3-like, C. elegans)
  • Gpt: glutamic-pyruvate transaminase (alanine aminotransferase)
  • Gramd1a: GRAM domain containing 1A
  • Grasp: GRP1 (general receptor for phosphoinositides 1)-associated scaffold protein
  • Grem1: gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
  • Gria1: glutamate receptor, ionotropic, AMPA 1
  • Grid2: glutamate receptor, ionotropic, delta 2
  • Grik1: glutamate receptor, ionotropic, kainate 1
  • Grik4: glutamate receptor, ionotropic, kainate 4
  • Grin2a: glutamate receptor, ionotropic, N-methyl D-aspartate 2A
  • Grin2b: glutamate receptor, ionotropic, N-methyl D-aspartate 2B
  • Grip1: glutamate receptor interacting protein 1
  • Gripap1: GRIP1 associated protein 1
  • Grk4: G protein-coupled receptor kinase 4
  • Grk5: G protein-coupled receptor kinase 5
  • Grk6: G protein-coupled receptor kinase 6
  • Grm4: glutamate receptor, metabotropic 4
  • Grm5: glutamate receptor, metabotropic 5
  • Grpel1: GrpE-like 1, mitochondrial (E. coli)
  • Gstk1: glutathione S-transferase kappa 1
  • Gstm2: glutathione S-transferase mu 2 (muscle)
  • Gsto1: glutathione S-transferase omega 1
  • Gtf2ird1: GTF2I repeat domain containing 1
  • Gtpbp4: GTP binding protein 4
  • Gucy1a2: guanylate cyclase 1, soluble, alpha 2
  • Gucy1a3: guanylate cyclase 1, soluble, alpha 3
  • Gucy1b2: guanylate cyclase 1, soluble, beta 2
  • Gucy2d: guanylate cyclase 2D, membrane (retina-specific)
  • Gulp1: GULP, engulfment adaptor PTB domain containing 1
  • Haao: 3-hydroxyanthranilate 3,4-dioxygenase
  • Itpka: inositol 1,4,5-trisphosphate 3-kinase A
  • Khdrbs2: KH domain containing, RNA binding, signal transduction associated 2
  • Kpnb1: karyopherin (importin) beta 1
  • Lamp2: lysosomal-associated membrane protein 2
  • Ncstn: nicastrin
  • Nedd4l: neural precursor cell expressed, developmentally down-regulated 4-like
  • Nip7: nuclear import 7 homolog (S. cerevisiae)
  • Nnat: neuronatin
  • Nos1: nitric oxide synthase 1 (neuronal)
  • Nox1: NADPH oxidase 1
  • Npepps: aminopeptidase puromycin sensitive
  • Nr1h3: nuclear receptor subfamily 1, group H, member 3
  • Nr1i2: nuclear receptor subfamily 1, group I, member 2
  • Nr6a1: nuclear receptor subfamily 6, group A, member 1
  • Nrcam: neuronal cell adhesion molecule
  • Nrd1: nardilysin (N-arginine dibasic convertase)
  • Ntn1: netrin 1
  • Nucb2: nucleobindin 2
  • Nudc: nuclear distribution gene C homolog (A. nidulans)
  • Nup35: nucleoporin 35 kDa
  • Nup54: nucleoporin 54 kDa
  • Nup98: nucleoporin 98 kDa
  • Oaz1: ornithine decarboxylase antizyme 1
  • Ocrl: oculocerebrorenal syndrome of Lowe
  • Oit3: oncoprotein induced transcript 3
  • Olfm2: olfactomedin 2
  • Opa1: optic atrophy 1 (autosomal dominant)
  • Oplah: 5-oxoprolinase (ATP-hydrolysing)
  • Oprd1: opioid receptor, delta 1
  • Orc4l: origin recognition complex, subunit 4-like (yeast)
  • Osmr: oncostatin M receptor
  • Oxr1: oxidation resistance 1
  • P2rx7: purinergic receptor P2X, ligand-gated ion channel, 7
  • P4hb: prolyl 4-hydroxylase, beta polypeptide
  • Pa2g4: proliferation-associated 2G4, 38 kDa
  • Pabpc4: poly(A) binding protein, cytoplasmic 4 (inducible form)
  • Pace4: proprotein convertase subtilisin/kexin type 6
  • Pacs1: phosphofurin acidic cluster sorting protein 1
  • Pafah1b2: platelet-activating factor acetylhydrolase, isoform Ib, subunit 2 (30 kDa)
  • Pafah1b3: platelet-activating factor acetylhydrolase, isoform Ib, subunit 3 (29 kDa)
  • Pak1: p21 protein (Cdc42/Rac)-activated kinase 1
  • Pak2: p21 protein (Cdc42/Rac)-activated kinase 2
  • Pak3: p21 protein (Cdc42/Rac)-activated kinase 3
  • Palm: paralemmin
  • Pamci: Ras association (RalGDS/AF-6) domain family (N-terminal) member 9
  • Panx1: pannexin 1
  • Panx2: pannexin 2
  • Pard3: par-3 partitioning defective 3 homolog (C. elegans)
  • Parg: poly (ADP-ribose) glycohydrolase
  • Park7: Parkinson disease (autosomal recessive, early onset) 7
  • Pawr: PRKC, apoptosis, WT1, regulator
  • Pax3: paired box 3
  • Pbp: phosphatidylethanolamine binding protein 1
  • Pc: pyruvate carboxylase
  • Pcca: propionyl Coenzyme A carboxylase, alpha polypeptide
  • Pcdh21: protocadherin 21
  • Pcdh7: protocadherin 7
  • Pcdha3: protocadherin alpha 3
  • Pcdhb1: protocadherin beta 1
  • Pck1: phosphoenolpyruvate carboxykinase 1 (soluble)
  • Pclo: piccolo (presynaptic cytomatrix protein)
  • Pcm1: pericentriolar material 1
  • Pcmt1: protein-L-isoaspartate (D-aspartate) O-methyltransferase
  • PCNT: pericentrin
  • Pcnx: pecanex homolog (Drosophila)
  • Pcnxl3: pecanex-like 3 (Drosophila)
  • Pcsk1: proprotein convertase subtilisin/kexin type 1
  • Pcsk1n: proprotein convertase subtilisin/kexin type 1 inhibitor
  • Pcsk5: proprotein convertase subtilisin/kexin type 5
  • Pcyox1: prenylcysteine oxidase 1
  • Pcyt1b: phosphate cytidylyltransferase 1, choline, beta
  • Pdap1: PDGFA associated protein 1
  • Pdc: phosducin
  • Pdcd2: programmed cell death 2
  • Pdcl: phosducin-like
  • Pde10a: phosphodiesterase 10A
  • Pde1a: phosphodiesterase 1A, calmodulin-dependent
  • Pde1c: phosphodiesterase 1C, calmodulin-dependent 70 kDa
  • Pde4a: phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 dunce homolog, Drosophila)
  • Pde4b: phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce homolog, Drosophila)
  • Pde4d: phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)
  • Pde5a: phosphodiesterase 5A, cGMP-specific
  • Pde7a: phosphodiesterase 7A
  • Pde7b: phosphodiesterase 7B
  • Pdgfra: platelet-derived growth factor receptor, alpha polypeptide
  • Pdhb: pyruvate dehydrogenase (lipoamide) beta
  • Pdia3: protein disulfide isomerase family A, member 3
  • Pdia4: protein disulfide isomerase family A, member 4
  • Pdk4: pyruvate dehydrogenase kinase, isozyme 4
  • Pdlim7: PDZ and LIM domain 7 (enigma)
  • Pds5b: PDS5, regulator of cohesion maintenance, homolog B (S. cerevisiae)
  • Pdzd3: PDZ domain containing 3
  • Pepd: peptidase D
  • Per3: period homolog 3 (Drosophila)
  • Pex14: peroxisomal biogenesis factor 14
  • Pfkl: phosphofructokinase, liver
  • Pfkm: phosphofructokinase, muscle
  • Pfkp: phosphofructokinase, platelet
  • Pgam1: phosphoglycerate mutase 1 (brain)
  • PGAP1: post-GPI attachment to proteins 1
  • Pgd: phosphogluconate dehydrogenase
  • Pgf: placental growth factor
  • Pgk1: phosphoglycerate kinase 1
  • Pgm1: phosphoglucomutase 1
  • Pgr: progesterone receptor
  • Pgrmc1: progesterone receptor membrane component 1
  • Phactr1: phosphatase and actin regulator 1
  • Phactr3: phosphatase and actin regulator 3
  • Phb: prohibitin
  • Phex: phosphate regulating endopeptidase homolog, X-linked
  • Phgdh: phosphoglycerate dehydrogenase
  • Phip: pleckstrin homology domain interacting protein
  • Phtf1: putative homeodomain transcription factor 1
  • Phyhipl: phytanoyl-CoA 2-hydroxylase interacting protein-like
  • Pi4ka: phosphatidylinositol 4-kinase, catalytic, alpha
  • Picalm: phosphatidylinositol binding clathrin assembly protein
  • Pigq: phosphatidylinositol glycan anchor biosynthesis, class Q
  • Pigs: phosphatidylinositol glycan anchor biosynthesis, class S
  • Pik3cg: phosphoinositide-3-kinase, catalytic, gamma polypeptide
  • Pip5k1a: phosphatidylinositol-4-phosphate 5-kinase, type I, alpha
  • Pip5k1c: phosphatidylinositol-4-phosphate 5-kinase, type I, gamma
  • Pip5k2a: phosphatidylinositol-5-phosphate 4-kinase, type II, alpha
  • Pip5k2c: phosphatidylinositol-5-phosphate 4-kinase, type II, gamma
  • Pipox: pipecolic acid oxidase
  • Pitpn: phosphatidylinositol transfer protein, alpha
  • Pkd1: polycystic kidney disease 1 (autosomal dominant)
  • Pkia: protein kinase (cAMP-dependent, catalytic) inhibitor alpha
  • Pkm2: pyruvate kinase, muscle
  • Pla2g4c: phospholipase A2, group IVC (cytosolic, calcium-independent)
  • Plaa: phospholipase A2-activating protein
  • Plau: plasminogen activator, urokinase
  • Plcb1: phospholipase C, beta 1 (phosphoinositide-specific)
  • Plcl1: phospholipase C-like 1
  • Pld3: phospholipase D family, member 3
  • Plekha4: pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 4
  • Plekhe1: PH domain and leucine rich repeat protein phosphatase 1
  • Plekhm1: pleckstrin homology domain containing, family M (with RUN domain) member 1
  • Plg: plasminogen
  • Plk1: polo-like kinase 1 (Drosophila)
  • Plrg1: pleiotropic regulator 1 (PRL1 homolog, Arabidopsis)
  • Plunc: palate, lung and nasal epithelium associated
  • Plvap: plasmalemma vesicle associated protein
  • Plxnb2: plexin B2
  • Pmpca: peptidase (mitochondrial processing) alpha
  • Pmvk: phosphomevalonate kinase
  • Pnliprp2: pancreatic lipase-related protein 2
  • Pnma1: paraneoplastic antigen MA1
  • Pno1: partner of NOB1 homolog (S. cerevisiae)
  • Pnpla2: patatin-like phospholipase domain containing 2
  • Pofut1: protein O-fucosyltransferase 1
  • Pon2: paraoxonase 2
  • Pon3: paraoxonase 3
  • Pop7: processing of precursor 7, ribonuclease P/MRP subunit (S. cerevisiae)
  • Por: P450 (cytochrome) oxidoreductase
  • Pou2f2: POU class 2 homeobox 2
  • Ppfia3: protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein, alpha 3
  • Ppgb: cathepsin A
  • Ppib: peptidylprolyl isomerase B (cyclophilin B)
  • Ppid: peptidylprolyl isomerase D
  • Ppil3: peptidylprolyl isomerase (cyclophilin)-like 3
  • Ppm2c: pyruvate dehydrogenase phosphatase catalytic subunit 1
  • Ppp1r10: protein phosphatase 1, regulatory (inhibitor) subunit 10
  • Ppp1r14b: protein phosphatase 1, regulatory (inhibitor) subunit 14B
  • Ppp1r14d: protein phosphatase 1, regulatory (inhibitor) subunit 14D
  • Ppp1r1a: protein phosphatase 1, regulatory (inhibitor) subunit 1A
  • Ppp1r7: protein phosphatase 1, regulatory (inhibitor) subunit 7
  • Ppp1r8: protein phosphatase 1, regulatory (inhibitor) subunit 8
  • Ppp1r9a: protein phosphatase 1, regulatory (inhibitor) subunit 9A
  • Ppp1r9b: protein phosphatase 1, regulatory (inhibitor) subunit 9B
  • Ppp2cb: protein phosphatase 2 (formerly 2A), catalytic subunit, beta isoform
  • Ppp2r1a: protein phosphatase 2 (formerly 2A), regulatory subunit A, alpha isoform
  • Ppp2r1b: protein phosphatase 2 (formerly 2A), regulatory subunit A, beta isoform
  • Ppp2r2a: protein phosphatase 2 (formerly 2A), regulatory subunit B, alpha isoform
  • PPP2R2B: protein phosphatase 2 (formerly 2A), regulatory subunit B, beta isoform
  • Ppp2r5e: protein phosphatase 2, regulatory subunit B', epsilon isoform
  • Ppp3cc: protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform
  • Ppp5c: protein phosphatase 5, catalytic subunit
  • Prdm4: PR domain containing 4
  • Prdx1: peroxiredoxin 1
  • Prep: prolyl endopeptidase
  • Prf1: perforin 1 (pore forming protein)
  • Prkaa2: protein kinase, AMP-activated, alpha 2 catalytic subunit
  • Prkaca: protein kinase, cAMP-dependent, catalytic, alpha
  • prkar1a: protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)
  • Prkar1a: protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)
  • Prkar2a: protein kinase, cAMP-dependent, regulatory, type II, alpha
  • Prkar2b: protein kinase, cAMP-dependent, regulatory, type II, beta
  • Prkca: protein kinase C, alpha
  • Prkcb1: protein kinase C, beta
  • Prkci: protein kinase C, iota
  • Prkcm: protein kinase D1
  • PRKCQ: protein kinase C, theta
  • Prkcz: protein kinase C, zeta
  • Prkwnk1: WNK lysine deficient protein kinase 1
  • Prmt3: protein arginine methyltransferase 3
  • Prnp: prion protein
  • Prom2: prominin 2
  • Prph2: peripherin 2 (retinal degeneration, slow)
  • Prpsap1: phosphoribosyl pyrophosphate synthetase-associated protein 1
  • Prpsap2: phosphoribosyl pyrophosphate synthetase-associated protein 2
  • Prr3: proline rich 3
  • Prrx2: paired related homeobox 2
  • Prrxl1: dorsal root ganglia homeobox
  • Prss1: protease, serine, 1 (trypsin 1)
  • Prss12: protease, serine, 12 (neurotrypsin, motopsin)
  • Prss15: lon peptidase 1, mitochondrial
  • Prtg: protogenin homolog (Gallus gallus)
  • Prx: periaxin
  • Psat1: phosphoserine aminotransferase 1
  • Psd: pleckstrin and Sec7 domain containing
  • Psd4: pleckstrin and Sec7 domain containing 4
  • Psmc1: proteasome (prosome, macropain) 26S subunit, ATPase, 1
  • Psmc3: proteasome (prosome, macropain) 26S subunit, ATPase, 3
  • Psmc5: proteasome (prosome, macropain) 26S subunit, ATPase, 5
  • Psmd1: proteasome (prosome, macropain) 26S subunit, non-ATPase, 1
  • Psme1: proteasome (prosome, macropain) activator subunit 1 (PA28 alpha)
  • Psme2: proteasome (prosome, macropain) activator subunit 2 (PA28 beta)
  • Psme3: proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki)
  • Psph: phosphoserine phosphatase
  • Ptbp1: polypyrimidine tract binding protein 1
  • Ptbp2: polypyrimidine tract binding protein 2
  • Ptger2: prostaglandin E receptor 2 (subtype EP2), 53 kDa
  • Ptgis: prostaglandin I2 (prostacyclin) synthase
  • Ptgs1: prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)
  • Pth: parathyroid hormone
  • Pthr2: parathyroid hormone 2 receptor
  • Ptk2: PTK2 protein tyrosine kinase 2
  • Ptn: pleiotrophin
  • Ptov1: prostate tumor overexpressed 1
  • Ptp4a1: protein tyrosine phosphatase type IVA, member 1
  • Ptpn11: protein tyrosine phosphatase, non-receptor type 11
  • Rnmt: RNA (guanine-7-) methyltransferase
  • Rraga: Ras-related GTP binding A
  • Rtn4: reticulon 4
  • Ryr3: ryanodine receptor 3
  • Sca1: ataxin 1
  • Sca10: ataxin 10
  • Scfd1: sec1 family domain containing 1
  • Scgb3a2: secretoglobin, family 3A, member 2
  • Scn1a: sodium channel, voltage-gated, type I, alpha subunit
  • Scn2a1: sodium channel, voltage-gated, type II, alpha subunit
  • Scp2: sterol carrier protein 2
  • Sdad1: SDA1 domain containing 1
  • Sdc2: syndecan 2
  • Sdcbp: syndecan binding protein (syntenin)
  • Sdfr1: neuroplastin
  • Sdha: succinate dehydrogenase complex, subunit A, flavoprotein (Fp)
  • Sec11l3: SEC11 homolog C (S. cerevisiae)
  • Sec31l1: SEC31 homolog A (S. cerevisiae)
  • Sectm1: secreted and transmembrane 1
  • Sema6c: sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6C
  • Sephs1: selenophosphate synthetase 1
  • Serinc3: serine incorporator 3
  • Serpinb3: serpin peptidase inhibitor, clade B (ovalbumin), member 3
  • Serpine2: serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2
  • Sez6: seizure related 6 homolog (mouse)
  • Sf3b1: splicing factor 3b, subunit 1, 155 kDa
  • Sfpq: splicing factor proline/glutamine-rich (polypyrimidine tract binding protein associated)
  • Sfrp4: secreted frizzled-related protein 4
  • Sfrs10: transformer 2 beta homolog (Drosophila)
  • Sfrs8: splicing factor, arginine/serine-rich 8 (suppressor-of-white-apricot homolog, Drosophila)
  • Sfrs9: splicing factor, arginine/serine-rich 9
  • Sftpb: surfactant protein B
  • Sfxn3: sideroflexin 3
  • Sfxn5: sideroflexin 5
  • Sgca: sarcoglycan, alpha (50 kDa dystrophin-associated glycoprotein)
  • Sgtb: small glutamine-rich tetratricopeptide repeat (TPR)-containing, beta
  • Sh2d4a: SH2 domain containing 4A
  • Sh3bp4: SH3-domain binding protein 4
  • Sh3bp5: SH3-domain binding protein 5 (BTK-associated)
  • Sh3gl3: SH3-domain GRB2-like 3
  • Sh3glb2: SH3-domain GRB2-like endophilin B2
  • Shank1: SH3 and multiple ankyrin repeat domains 1
  • Shank2: SH3 and multiple ankyrin repeat domains 2
  • Shc1: SHC (Src homology 2 domain containing) transforming protein 1
  • Shh: sonic hedgehog homolog (Drosophila)
  • Shoc2: soc-2 suppressor of clear homolog (C. elegans)
  • Siat7A: ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1
  • Sipa1: signal-induced proliferation-associated 1
  • Sipa1l2: signal-induced proliferation-associated 1 like 2
  • Sipa1l3: signal-induced proliferation-associated 1 like 3
  • Sirpa: signal-regulatory protein alpha
  • Sirt2: sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)
  • Sirt5: sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae)
  • Slc11a2: solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2
  • Slc12a1: solute carrier family 12 (sodium/potassium/chloride transporters), member 1
  • Slc12a5: solute carrier family 12 (potassium-chloride transporter), member 5
  • Slco3a1: solute carrier organic anion transporter family, member 3A1
  • Slit1: slit homolog 1 (Drosophila)
  • Slit2: slit homolog 2 (Drosophila)
  • Slit3: slit homolog 3 (Drosophila)
  • Slk: STE20-like kinase (yeast)
  • Slu7: SLU7 splicing factor homolog (S. cerevisiae)
  • Smad1: SMAD family member 1
  • Smarca2: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2
  • Smc1l1: structural maintenance of chromosomes 1A
  • Smo: smoothened homolog (Drosophila)
  • Smoc1: SPARC related modular calcium binding 1
  • Smu1: smu-1 suppressor of mec-8 and unc-52 homolog (C. elegans)
  • Sn: sialic acid binding Ig-like lectin 1, sialoadhesin
  • Snai1: snail homolog 1 (Drosophila)
  • Snai2: snail homolog 2 (Drosophila)
  • Snap23: synaptosomal-associated protein, 23 kDa
  • Snap25: synaptosomal-associated protein, 25 kDa
  • Snap91: synaptosomal-associated protein, 91 kDa homolog (mouse)
  • Snca: synuclein, alpha (non A4 component of amyloid precursor)
  • Sncb: synuclein, beta
  • Snd1: staphylococcal nuclease and tudor domain containing 1
  • Snph: syntaphilin
  • Snrk: SNF related kinase
  • Snx17: sorting nexin 17
  • Snx25: sorting nexin 25
  • Snx3: sorting nexin 3
  • Soat1: sterol O-acyltransferase 1
  • Socs1: suppressor of cytokine signaling 1
  • SOD1: superoxide dismutase 1, soluble
  • Sod2: superoxide dismutase 2, mitochondrial
  • Sord: sorbitol dehydrogenase
  • Sox10: SRY (sex determining region Y)-box 10
  • Sp2: Sp2 transcription factor
  • Sparc: secreted protein, acidic, cysteine-rich (osteonectin)
  • Spata20: spermatogenesis associated 20
  • Spint1: serine peptidase inhibitor, Kunitz type 1
  • Spp1: secreted phosphoprotein 1
  • Spsb4: splA/ryanodine receptor domain and SOCS box containing 4
  • Sqle: squalene epoxidase
  • Src: v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)
  • Srd5a2: steroid-5-alpha-reductase, alpha polypeptide 2
  • Srebf1: sterol regulatory element binding transcription factor 1
  • Srprb: signal recognition particle receptor, B subunit
  • Ssb: Sjogren syndrome antigen B (autoantigen La)
  • Ssr4: signal sequence receptor, delta (translocon-associated protein delta)
  • Ssrp1: structure specific recognition protein 1
  • Sstr2: somatostatin receptor 2
  • Ssx2ip: synovial sarcoma, X breakpoint 2 interacting protein
  • St14: suppression of tumorigenicity 14 (colon carcinoma)
  • St18: suppression of tumorigenicity 18 (breast carcinoma) (zinc finger protein)
  • St3gal1: ST3 beta-galactoside alpha-2,3-sialyltransferase 1
  • St6gal2: ST6 beta-galactosamide alpha-2,6-sialyltransferase 2
  • St7: suppression of tumorigenicity 7
  • St7l: suppression of tumorigenicity 7 like
  • Star: steroidogenic acute regulatory protein
  • Stard3nl: STARD3 N-terminal like
  • Stat1: signal transducer and activator of transcription 1, 91 kDa
  • Stat3: signal transducer and activator of transcription 3 (acute-phase response factor)
  • Stau1: staufen, RNA binding protein, homolog 1 (Drosophila)
  • Stch: heat shock protein 70 kDa family, member 13
  • Ste: sulfotransferase family 1E, estrogen-preferring, member 1
  • Stim2: stromal interaction molecule 2
  • Stip1: stress-induced-phosphoprotein 1
  • Stk10: serine/threonine kinase 10
  • Stk11: serine/threonine kinase 11
  • Stmn1: stathmin 1
  • Stmn2: stathmin-like 2
  • Stmn3: stathmin-like 3
  • Stmn4: stathmin-like 4
  • Stnl: eukaryotic translation elongation factor 1 alpha 2
  • Stom: stomatin
  • Strbp: spermatid perinuclear RNA binding protein
  • Strn: striatin, calmodulin binding protein
  • Stx12: syntaxin 12
  • Stx1a: syntaxin 1A (brain)
  • Stx4a: syntaxin 4
  • Stx5a: syntaxin 5
  • Stx6: syntaxin 6
  • Stx8: syntaxin 8
  • Stxbp3: syntaxin binding protein 3
  • Stxbp5: syntaxin binding protein 5 (tomosyn)
  • Suclg1: succinate-CoA ligase, alpha subunit
  • Sult1a1: sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1
  • Sult1c1: sulfotransferase family, cytosolic, 1C, member 2
  • Sult1c2: sulfotransferase family, cytosolic, 1C, member 2
  • Sult1e1: sulfotransferase family 1E, estrogen-preferring, member 1
  • Sult4a1: sulfotransferase family 4A, member 1
  • Supv3l1: suppressor of var1, 3-like 1 (S. cerevisiae)
  • Surf6: surfeit 6
  • Suv420h2: suppressor of variegation 4-20 homolog 2 (Drosophila)
  • Sv2a: synaptic vesicle glycoprotein 2A
  • Sv2b: synaptic vesicle glycoprotein 2B
  • Sycp1: synaptonemal complex protein 1
  • Sycp2: synaptonemal complex protein 2
  • Syn1: synapsin I
  • Syn2: synapsin II
  • Syn3: synapsin III
  • Syngap1: synaptic Ras GTPase activating protein 1 homolog (rat)
  • Synj1: synaptojanin 1
  • Synj2: synaptojanin 2
  • Synj2bp: synaptojanin 2 binding protein
  • Synpo: synaptopodin
  • Sypl: synaptophysin-like 1
  • Syt11: synaptotagmin XI
  • Syt12: synaptotagmin XII
  • Syt5: synaptotagmin V
  • Syt6: synaptotagmin VI
  • Syt8: synaptotagmin VIII
  • Tacc1: transforming, acidic coiled-coil containing protein 1
  • Tacc2: transforming, acidic coiled-coil containing protein 2
  • Tacr1: tachykinin receptor 1
  • Taf1c: TATA box binding protein (TBP)-associated factor, RNA polymerase I, C, 110 kDa
  • Taf9l: TAF9B RNA polymerase II, TATA box binding protein (TBP)-associated factor, 31 kDa
  • Tagln: transgelin
  • Tagln3: transgelin 3
  • Taldo1: transaldolase 1
  • Taok1: TAO kinase 1
  • Tapbp: TAP binding protein (tapasin)
  • Tars: threonyl-tRNA synthetase
  • Tas2r41: taste receptor, type 2, member 41
  • Tat: tyrosine aminotransferase
  • Tax1bp1: Tax1 (human T-cell leukemia virus type I) binding protein 1
  • Tbc1d10b: TBC1 domain family, member 10B
  • Tbca: tubulin folding cofactor A
  • Tbx2: T-box 2
  • Tcirg1: T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3
  • Tcn2: transcobalamin II; macrocytic anemia
  • Tcp1: t-complex 1
  • Tcra: T cell receptor alpha locus
  • Tdg: thymine-DNA glycosylase
  • Tdrd7: tudor domain containing 7
  • Tead1: TEA domain family member 1 (SV40 transcriptional enhancer factor)
  • Tegt: transmembrane BAX inhibitor motif containing 6
  • Tg: thyroglobulin
  • Tgfb1: transforming growth factor, beta 1
  • Tgfbr3: transforming growth factor, beta receptor III
  • Tgm1: transglutaminase 1 (K polypeptide epidermal type I, protein-glutamine-gamma-glutamyltransferase)
  • Tgm2: transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)
  • Thbd: thrombomodulin
  • Thbs4: thrombospondin 4
  • Thpo: thrombopoietin
  • Thra: thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian)
  • Thrap3: thyroid hormone receptor associated protein 3
  • Thrb: thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian)
  • Thy1: Thy-1 cell surface antigen
  • Tigd3: tigger transposable element derived 3
  • Timm44: translocase of inner mitochondrial membrane 44 homolog (yeast)
  • Timm8a: translocase of inner mitochondrial membrane 8 homolog A (yeast)
  • Tinag: tubulointerstitial nephritis antigen
  • Tjp1: tight junction protein 1 (zona occludens 1)
  • Tjp2: tight junction protein 2 (zona occludens 2)
  • Tkt: transketolase
  • Tle3: transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila)
  • Tlr3: toll-like receptor 3
  • Tlr4: toll-like receptor 4
  • Tlr5: toll-like receptor 5
  • Tlr6: toll-like receptor 6
  • Tlr9: toll-like receptor 9
  • Tm4sf8: tetraspanin 3
  • Tm9sf2: transmembrane 9 superfamily member 2
  • Tm9sf3: transmembrane 9 superfamily member 3
  • Tmco1: transmembrane and coiled-coil domains 1
  • Tmeff1: transmembrane protein with EGF-like and two follistatin-like domains 1
  • Tmem27: transmembrane protein 27
  • Tmf1: TATA element modulatory factor 1
  • Tmpo: thymopoietin
  • Tmsb10: thymosin beta 10
  • Tnfaip1: tumor necrosis factor, alpha-induced protein 1 (endothelial)
  • Tnni1: troponin I type 1 (skeletal, slow)
  • Tnni2: troponin I type 2 (skeletal, fast)
  • Tnnt3: troponin T type 3 (skeletal, fast)
  • Tob1: transducer of ERBB2, 1
  • Tob2: transducer of ERBB2, 2
  • Tom1: target of myb1 (chicken)
  • Tor3a: torsin family 3, member A
  • Tpbg: trophoblast glycoprotein
  • Tpd52l2: tumor protein D52-like 2
  • Tph2: tryptophan hydroxylase 2
  • Tpm3: tropomyosin 3
  • Tpo: thyroid peroxidase
  • Tpst2: tyrosylprotein sulfotransferase 2
  • Tpt1: tumor protein, translationally-controlled 1
  • Tr4: nuclear receptor subfamily 2, group C, member 2
  • Traf3ip1: TNF receptor-associated factor 3 interacting protein 1
  • Trak2: trafficking protein, kinesin binding 2
  • Trap1: TNF receptor-associated protein 1
  • Trib3: tribbles homolog 3 (Drosophila)
  • Trim13: tripartite motif-containing 13
  • Trim54: tripartite motif-containing 54
  • Trip10: thyroid hormone receptor interactor 10
  • Trpc2: transient receptor potential cation channel, subfamily C, member 2 (pseudogene)
  • Trpc4: transient receptor potential cation channel, subfamily C, member 4
  • Trpc5: transient receptor potential cation channel, subfamily C, member 5
  • Trpc7: transient receptor potential cation channel, subfamily C, member 7
  • Trpv1: transient receptor potential cation channel, subfamily V, member 1
  • Trpv4: transient receptor potential cation channel, subfamily V, member 4
  • Tsc1: tuberous sclerosis 1
  • Tsc2: tuberous sclerosis 2
  • Tsg101: tumor susceptibility gene 101
  • Tsga10: testis specific, 10
  • Tsga10ip: testis specific, 10 interacting protein
  • Tshr: thyroid stimulating hormone receptor
  • Tsn: translin
  • Tsnax: translin-associated factor X
  • Tst: thiosulfate sulfurtransferase (rhodanese)
  • Ttc1: tetratricopeptide repeat domain 1
  • Ttn: titin
  • Tub: tubby homolog (mouse)
  • Tuba1a: tubulin, alpha 1a
  • Tubb2b: tubulin, beta 2B
  • Tubb2c: tubulin, beta 2C
  • Tubb3: tubulin, beta 3
  • Tusc3: tumor suppressor candidate 3
  • Txn: thioredoxin
  • Txn2: thioredoxin 2
  • Txndc4: endoplasmic reticulum protein 44
  • Txnip: thioredoxin interacting protein
  • Txnl2: glutaredoxin 3
  • Txnrd1: thioredoxin reductase 1
  • Txnrd2: thioredoxin reductase 2
  • Ubc: ubiquitin C
  • Ube2e2: ubiquitin-conjugating enzyme E2E 2 (UBC4/5 homolog, yeast)
  • Ubl3: ubiquitin-like 3
  • Ubqln1: ubiquilin 1
  • Ubxd3: UBX domain protein 10
  • Uchl1: ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
  • Ucp1: uncoupling protein 1 (mitochondrial, proton carrier)
  • Ucp2: uncoupling protein 2 (mitochondrial, proton carrier)
  • Ugt1a1: UDP glucuronosyltransferase 1 family, polypeptide A1
  • Umod: uromodulin
  • Unc13a: unc-13 homolog A (C. elegans)
  • Unc13b: unc-13 homolog B (C. elegans)
  • Unc13c: unc-13 homolog C (C. elegans)
  • Unc5b: unc-5 homolog B (C. elegans)
  • Uqcrc2: ubiquinol-cytochrome c reductase core protein II
  • Uqcrfs1: ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1
  • Uso1: USO1 homolog, vesicle docking protein (yeast)
  • Usp11: ubiquitin specific peptidase 11
  • Vamp1: vesicle-associated membrane protein 1 (synaptobrevin 1)
  • Vamp2: vesicle-associated membrane protein 2 (synaptobrevin 2)
  • Vamp3: vesicle-associated membrane protein 3 (cellubrevin)
  • Vapa: VAMP (vesicle-associated membrane protein)-associated protein A, 33 kDa
  • Vapb: VAMP (vesicle-associated membrane protein)-associated protein B and C
  • VCAN: versican
  • Vcan: versican
  • Vcp: valosin-containing protein
  • Vcpip1: valosin containing protein (p97)/p47 complex interacting protein 1
  • Vdac1: voltage-dependent anion channel 1
  • Vdac2: voltage-dependent anion channel 2
  • Vegfa: vascular endothelial growth factor A
  • Vgcnl1: sodium leak channel, non-selective
  • Vgf: VGF nerve growth factor inducible
  • Vipr2: vasoactive intestinal peptide receptor 2
  • Vpreb1: pre-B lymphocyte 1
  • Vps33a: vacuolar protein sorting 33 homolog A (S. cerevisiae)
  • Vps33b: vacuolar protein sorting 33 homolog B (yeast)
  • Vps4a: vacuolar protein sorting 4 homolog A (S. cerevisiae)
  • Vsnl1: visinin-like 1
  • Vtn: vitronectin
  • Wars: tryptophanyl-tRNA synthetase
  • Wbp2: WW domain binding protein 2
  • Wdr10: intraflagellar transport 122 homolog (Chlamydomonas)
  • Wdr44: WD repeat domain 44
  • Wdr7: WD repeat domain 7
  • Wfs1: Wolfram syndrome 1 (wolframin)
  • Wif1: WNT inhibitory factor 1
  • Wipf1: WAS/WASL interacting protein family, member 1
  • Wnk4: WNK lysine deficient protein kinase 4
  • Wnt5a: wingless-type MMTV integration site family, member 5A
  • Wnt7a: wingless-type MMTV integration site family, member 7A
  • Xkr6: XK, Kell blood group complex subunit-related family, member 6
  • Xpnpep2: X-prolyl aminopeptidase (aminopeptidase P) 2, membrane-bound
  • Xpo1: exportin 1 (CRM1 homolog, yeast)
  • Xpo6: exportin 6
  • Xrcc1: X-ray repair complementing defective repair in Chinese hamster cells 1
  • Xrcc5: X-ray repair complementing defective repair in Chinese hamster cells 5
  • Xylt1: xylosyltransferase I
  • Yars2: tyrosyl-tRNA synthetase 2, mitochondrial
  • Yes1: v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1
  • Ykt6: YKT6 v-SNARE homolog (S. cerevisiae)
  • Ywhab: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide
  • Yy1: YY1 transcription factor
  • Znf382: zinc finger protein 382
  • Zranb1: zinc finger, RAN-binding domain containing 1
  • Zwint: ZW10 interactor.

B.

Lipid raft-derived extracted proteins from Alzheimer's disease (3xTgAD) mouse 16-month-old cortical tissue. Specific proteins isolated from 3xTgAD mouse cortex were identified with multidimensional protein identification technology (MudPIT) LC MS/MS. Each protein was identified in at least two out of three experimental replicate animals and from at least two isolated peptides per protein. The following are the protein symbol and its corresponding definition.

  • Abca1: ATP-binding cassette, sub-family A (ABC1), member 1
  • ABCA7: ATP-binding cassette, sub-family A (ABC1), member 7
  • Abcb4: ATP-binding cassette, sub-family B (MDR/TAP), member 4
  • Abcc1: ATP-binding cassette, sub-family C (CFTR/MRP), member 1
  • Abcc2: ATP-binding cassette, sub-family C (CFTR/MRP), member 2
  • Abcc4: ATP-binding cassette, sub-family C (CFTR/MRP), member 4
  • Abi1: abl-interactor 1
  • Acadl: acyl-Coenzyme A dehydrogenase, long chain
  • Acat1: acetyl-Coenzyme A acetyltransferase 1
  • Acin1: apoptotic chromatin condensation inducer 1
  • Acmsd: aminocarboxymuconate semialdehyde decarboxylase
  • Acp2: acid phosphatase 2, lysosomal
  • Acta1: actin, alpha 1, skeletal muscle
  • Actb: actin, beta
  • Actn4: actinin, alpha 4
  • Acvr1: activin A receptor, type I
  • Adam2: ADAM metallopeptidase domain 2
  • Adam6: ADAM metallopeptidase domain 6 (pseudogene)
  • Adcy1: adenylate cyclase 1 (brain)
  • Adcy5: adenylate cyclase 5
  • Adcy8: adenylate cyclase 8 (brain)
  • Adcyap1: adenylate cyclase activating polypeptide 1 (pituitary)
  • Adcyap1r1: adenylate cyclase activating polypeptide 1 (pituitary) receptor type I
  • Add1: adducin 1 (alpha)
  • Add2: adducin 2 (beta)
  • Adrbk1: adrenergic, beta, receptor kinase 1
  • Aes: amino-terminal enhancer of split
  • Agpat1: 1-acylglycerol-3-phosphate O-acyltransferase 1 (lysophosphatidic acid acyltransferase, alpha)
  • Agpat4: 1-acylglycerol-3-phosphate O-acyltransferase 4 (lysophosphatidic acid acyltransferase, delta)
  • Agrn: agrin
  • Ahi1: Abelson helper integration site 1
  • Ahr: aryl hydrocarbon receptor
  • Ahrr: aryl-hydrocarbon receptor repressor
  • Ak3: adenylate kinase 3
  • Akap12: A kinase (PRKA) anchor protein 12
  • Akap3: A kinase (PRKA) anchor protein 3
  • Akap4: A kinase (PRKA) anchor protein 4
  • Akap9: A kinase (PRKA) anchor protein (yotiao) 9
  • Alad: aminolevulinate, delta-, dehydratase
  • Aldh1a3: aldehyde dehydrogenase 1 family, member A3
  • Alox5: arachidonate 5-lipoxygenase
  • Ampd1: adenosine monophosphate deaminase 1 (isoform M)
  • Anxa3: annexin A3
  • Anxa6: annexin A6
  • Apex2: APEX nuclease (apurinic/apyrimidinic endonuclease) 2
  • Apob: apolipoprotein B (including Ag(x) antigen)
  • Apod: apolipoprotein D
  • App: amyloid beta (A4) precursor protein
  • Aps: kallikrein-related peptidase 3
  • Aqp3: aquaporin 3 (Gill blood group)
  • Aqp4: aquaporin 4
  • Aqp8: aquaporin 8
  • Arf1: ADP-ribosylation factor 1
  • Arf4: ADP-ribosylation factor 4
  • Arf6: ADP-ribosylation factor 6
  • Arfip1: ADP-ribosylation factor interacting protein 1
  • Arhgap20: Rho GTPase activating protein 20
  • Arhgap8: Rho GTPase activating protein 8
  • Arhgdia: Rho GDP dissociation inhibitor (GDI) alpha
  • Arhgef11: Rho guanine nucleotide exchange factor (GEF) 11
  • Arhgef12: Rho guanine nucleotide exchange factor (GEF) 12
  • Arhgef6: Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6
  • Arnt: aryl hydrocarbon receptor nuclear translocator
  • Arntl: aryl hydrocarbon receptor nuclear translocator-like
  • Arpp19: cAMP-regulated phosphoprotein, 19 kDa
  • Ascc1: activating signal cointegrator 1 complex subunit 1
  • Asz1: ankyrin repeat, SAM and basic leucine zipper domain containing 1
  • Atcay: ataxia, cerebellar, Cayman type
  • Atf3: activating transcription factor 3
  • Atm: ataxia telangiectasia mutated
  • Atp1a1: ATPase, Na+/K+ transporting, alpha 1 polypeptide
  • Atp1a4: ATPase, Na+/K+ transporting, alpha 4 polypeptide
  • Atp1b1: ATPase, Na+/K+ transporting, beta 1 polypeptide
  • ATP2B1: ATPase, Ca++ transporting, plasma membrane 1
  • Atp2b1: ATPase, Ca++ transporting, plasma membrane 1
  • Atp2b2: ATPase, Ca++ transporting, plasma membrane 2
  • Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1, cardiac muscle
  • Atp5b: ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide
  • Atp5f1: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit B1
  • Atp5h: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d
  • Atp5i: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit E
  • Atp5j: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F6
  • Atp6b2: ATPase, H+ transporting, lysosomal 56/58 kDa, V1 subunit B2
  • Atp6l: ATPase, H+ transporting, lysosomal 16 kDa, V0 subunit c
  • Atp6v0a1: ATPase, H+ transporting, lysosomal V0 subunit a1
  • ATPBD1C: GPN-loop GTPase 3
  • Atxn3: ataxin 3
  • Avil: advillin
  • B3gat1: beta-1,3-glucuronyltransferase 1 (glucuronosyltransferase P)
  • Bace1: beta-site APP-cleaving enzyme 1
  • Basp1: brain abundant, membrane attached signal protein 1
  • Bat2: HLA-B associated transcript 2
  • Bat5: HLA-B associated transcript 5
  • Bax: BCL2-associated X protein
  • Bcl10: B-cell CLL/lymphoma 10
  • Begain: brain-enriched guanylate kinase-associated homolog (rat)
  • Bmp6: bone morphogenetic protein 6
  • Bnip1: BCL2/adenovirus E1B 19 kDa interacting protein 1
  • Bnip3: BCL2/adenovirus E1B 19 kDa interacting protein 3
  • Bpnt1: 3'(2'), 5'-bisphosphate nucleotidase 1
  • Brd2: bromodomain containing 2
  • Brd8: bromodomain containing 8
  • Bst1: bone marrow stromal cell antigen 1
  • Btg2: BTG family, member 2
  • Bzrap1: benzodiazepine receptor (peripheral) associated protein 1
  • c3orf6: coiled-coil domain containing 50
  • C4a: complement component 4A (Rodgers blood group)
  • c8b: complement component 8, beta polypeptide
  • Cabc1: chaperone, ABC1 activity of bc1 complex homolog (S. pombe)
  • Cabin1: calcineurin binding protein 1
  • Cacna1g: calcium channel, voltage-dependent, T type, alpha 1G subunit
  • Cacna2d1: calcium channel, voltage-dependent, alpha 2/delta subunit 1
  • Cacna2d2: calcium channel, voltage-dependent, alpha 2/delta subunit 2
  • Cacna2d3: calcium channel, voltage-dependent, alpha 2/delta subunit 3
  • Cacnb2: calcium channel, voltage-dependent, beta 2 subunit
  • Calb1: calbindin 1, 28 kDa
  • Calb2: calbindin 2
  • Cald1: caldesmon 1
  • calm2: calmodulin 2 (phosphorylase kinase, delta)
  • Calr: calreticulin
  • Camk2g: calcium/calmodulin-dependent protein kinase II gamma
  • Camkk1: calcium/calmodulin-dependent protein kinase kinase 1, alpha
  • Camkv: CaM kinase-like vesicle-associated
  • Canx: calnexin
  • Cap1: CAP, adenylate cyclase-associated protein 1 (yeast)
  • Capn1: calpain 1, (mu/l) large subunit
  • Capn5: calpain 5
  • Capn6: calpain 6
  • Capzb: capping protein (actin filament) muscle Z-line, beta
  • Card9: caspase recruitment domain family, member 9
  • Carhsp1: calcium regulated heat stable protein 1, 24 kDa
  • Caskin1: CASK interacting protein 1
  • Casp7: caspase 7, apoptosis-related cysteine peptidase
  • Cast: calpastatin
  • Cbp: opsin 1 (cone pigments), long-wave-sensitive
  • Cbx3: chromobox homolog 3 (HP1 gamma homolog, Drosophila)
  • Ccnd2: cyclin D2
  • Ccs: copper chaperone for superoxide dismutase
  • Cct2: chaperonin containing TCP1, subunit 2 (beta)
  • Cd2ap: CD2-associated protein
  • Cd36: CD36 molecule (thrombospondin receptor)
  • Cd86: CD86 molecule
  • Cdc25b: cell division cycle 25 homolog B (S. pombe)
  • Cdc42: cell division cycle 42 (GTP binding protein, 25 kDa)
  • Cdc5l: CDC5 cell division cycle 5-like (S. pombe)
  • Cdh1: cadherin 1, type 1, E-cadherin (epithelial)
  • Cdh10: cadherin 10, type 2 (T2-cadherin)
  • Cdh13: cadherin 13, H-cadherin (heart)
  • Cdh2: cadherin 2, type 1, N-cadherin (neuronal)
  • Cdk5rap2: CDK5 regulatory subunit associated protein 2
  • Cdkn1b: cyclin-dependent kinase inhibitor 1B (p27, Kip1)
  • Cds1: CDP-diacylglycerol synthase (phosphatidate cytidylyltransferase) 1
  • Cdv1: intraflagellar transport 81 homolog (Chlamydomonas)
  • Cebp: CCAAT/enhancer binding protein (C/EBP), alpha
  • Cend1: cell cycle exit and neuronal differentiation 1
  • Cenpc1: centromere protein C 1
  • Cenpi: centromere protein I
  • Centa1: ArfGAP with dual PH domains 1
  • Ces1: carboxylesterase 1 (monocyte/macrophage serine esterase 1)
  • Cetn2: centrin, EF-hand protein, 2
  • Cfd: complement factor D (adipsin)
  • Cfl1: cofilin 1 (nonmuscle)
  • Cftr: cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)
  • Chgb: chromogranin B (secretogranin 1)
  • Chka: choline kinase alpha
  • Chm: choroideremia (Rab escort protein 1)
  • Chst10: carbohydrate sulfotransferase 10
  • Chx10: visual system homeobox 2
  • Cktsf1b1: gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
  • Clcf1: cardiotrophin-like cytokine factor 1
  • Cldn18: claudin 18
  • Clic4: chloride intracellular channel 4
  • Clip3: CAP-GLY domain containing linker protein 3
  • Clta: clathrin, light chain (Lca)
  • Cltb: clathrin, light chain (Lcb)
  • Cltc: clathrin, heavy chain (Hc)
  • Clu: clusterin
  • Cnga1: cyclic nucleotide gated channel alpha 1
  • Cngb1: cyclic nucleotide gated channel beta 1
  • Cnot4: CCR4-NOT transcription complex, subunit 4
  • Cnr1: cannabinoid receptor 1 (brain)
  • Col5a3: collagen, type V, alpha 3
  • Copb1: coatomer protein complex, subunit beta 1
  • Cops4: COP9 constitutive photomorphogenic homolog subunit 4 (Arabidopsis)
  • Coro1a: coronin, actin binding protein, 1A
  • Cp: ceruloplasmin (ferroxidase)
  • Cpa2: carboxypeptidase A2 (pancreatic)
  • Cpt2: carnitine palmitoyltransferase 2
  • Creb1: cAMP responsive element binding protein 1
  • Crhbp: corticotropin releasing hormone binding protein
  • Crip2: cysteine-rich protein 2
  • Cript: cysteine-rich PDZ-binding protein
  • Crmp1: collapsin response mediator protein 1
  • Cry2: cryptochrome 2 (photolyase-like)
  • Csf1: colony stimulating factor 1 (macrophage)
  • Csh1: chorionic somatomammotropin hormone 1 (placental lactogen)
  • Csnk1e: casein kinase 1, epsilon
  • Csnk1g1: casein kinase 1, gamma 1
  • Csnk1g3: casein kinase 1, gamma 3
  • Cspg6: structural maintenance of chromosomes 3
  • Cst6: cystatin E/M
  • Cstb: cystatin B (stefin B)
  • Ctnnb1: catenin (cadherin-associated protein), beta 1, 88 kDa
  • Cttn: cortactin
  • Cugbp2: CUG triplet repeat, RNA binding protein 2
  • Cul5: cullin 5
  • Cutl1: cut-like homeobox 1
  • Cxadr: coxsackie virus and adenovirus receptor
  • Cxcl10: chemokine (C-X-C motif) ligand 10
  • Cyb5r4: cytochrome b5 reductase 4
  • Cyln2: CAP-GLY domain containing linker protein 2
  • Cyp19a1: cytochrome P450, family 19, subfamily A, polypeptide 1
  • Cyp1a1: cytochrome P450, family 1, subfamily A, polypeptide 1
  • Cyp4x1: cytochrome P450, family 4, subfamily X, polypeptide 1
  • Dab2ip: DAB2 interacting protein
  • Dbn1: drebrin 1
  • Dctn1: dynactin 1 (p150, glued homolog, Drosophila)
  • Dctn2: dynactin 2 (p50)
  • Dctn4: dynactin 4 (p62)
  • Dcxr: dicarbonyl/L-xylulose reductase
  • Ddah2: dimethylarginine dimethylaminohydrolase 2
  • Ddb1: damage-specific DNA binding protein 1, 127 kDa
  • Ddt: D-dopachrome tautomerase
  • Ddx1: DEAD (Asp-Glu-Ala-Asp) box polypeptide 1
  • Ddx19: DEAD (Asp-Glu-Ala-As) box polypeptide 19B
  • Ddx27: DEAD (Asp-Glu-Ala-Asp) box polypeptide 27
  • Ddx5: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5
  • Dedd: death effector domain containing
  • Degs1: degenerative spermatocyte homolog 1, lipid desaturase (Drosophila)
  • Des: desmin
  • Dgkg: diacylglycerol kinase, gamma 90 kDa
  • Dhcr7: 7-dehydrocholesterol reductase
  • Dhodh: dihydroorotate dehydrogenase
  • Dhx40: DEAH (Asp-Glu-Ala-His) box polypeptide 40
  • Dia1: cytochrome b5 reductase 3
  • Disc1: disrupted in schizophrenia 1
  • Dkc1: dyskeratosis congenita 1, dyskerin
  • Dlat: dihydrolipoamide S-acetyltransferase
  • Dlc1: deleted in liver cancer 1
  • Dlgap2: discs, large (Drosophila) homolog-associated protein 2
  • Dlgap4: discs, large (Drosophila) homolog-associated protein 4
  • Dll1: delta-like 1 (Drosophila)
  • Dnah7: dynein, axonemal, heavy chain 7
  • Dnah9: dynein, axonemal, heavy chain 9
  • Dnajc5: DnaJ (Hsp40) homolog, subfamily C, member 5
  • Dnch1: dynein, cytoplasmic 1, heavy chain 1
  • Dnch2: dynein, cytoplasmic 2, heavy chain 1
  • Dnm1: dynamin 1
  • Dnmt1: DNA (cytosine-5-)-methyltransferase 1
  • Dnmt3a: DNA (cytosine-5-)-methyltransferase 3 alpha
  • Dntt: deoxynucleotidyltransferase, terminal
  • Dpp3: dipeptidyl-peptidase 3
  • Dpp6: dipeptidyl-peptidase 6
  • Dpyd: dihydropyrimidine dehydrogenase
  • Drd1ip: calcyon neuron-specific vesicular protein
  • Drg1: developmentally regulated GTP binding protein 1
  • Dtnb: dystrobrevin, beta
  • Dtnbp1: dystrobrevin binding protein 1
  • Duox1: dual oxidase 1
  • Dvl1: dishevelled, dsh homolog 1 (Drosophila)
  • Dyx1c1: dyslexia susceptibility 1 candidate 1
  • Eaf2: ELL associated factor 2
  • Echs1: enoyl Coenzyme A hydratase, short chain, 1, mitochondrial
  • Eef1g: eukaryotic translation elongation factor 1 gamma
  • Eef2: eukaryotic translation elongation factor 2
  • Eef2k: eukaryotic elongation factor-2 kinase
  • Efemp2: EGF-containing fibulin-like extracellular matrix protein 2
  • Egfr: epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)
  • Eif2ak3: eukaryotic translation initiation factor 2-alpha kinase 3
  • Eif2b1: eukaryotic translation initiation factor 2B, subunit 1 alpha, 26 kDa
  • Eif2c2: eukaryotic translation initiation factor 2C, 2
  • Eif2s2: eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDa
  • eif4a1: eukaryotic translation initiation factor 4A, isoform 1
  • Elavl3: ELAV (embryonic lethal, abnormal vision, Drosophila)-like 3 (Hu antigen C)
  • ELK1: ELK1, member of ETS oncogene family
  • Emd: emerin
  • Eno2: enolase 2 (gamma, neuronal)
  • Enpp2: ectonucleotide pyrophosphatase/phosphodiesterase 2
  • Entpd8: ectonucleoside triphosphate diphosphohydrolase 8
  • Ephx2: epoxide hydrolase 2, cytoplasmic
  • Epn1: epsin 1
  • Erp29: endoplasmic reticulum protein 29
  • Esd: esterase D/formylglutathione hydrolase
  • Espn: espin
  • Esrrb: estrogen-related receptor beta
  • Etfa: electron-transfer-flavoprotein, alpha polypeptide
  • Etfb: electron-transfer-flavoprotein, beta polypeptide
  • Exoc7: exocyst complex component 7
  • Ezr: ezrin
  • F5: coagulation factor V (proaccelerin, labile factor)
  • Fabp1: fatty acid binding protein 1, liver
  • Fancd2: Fanconi anemia, complementation group D2
  • Fat: FAT tumor suppressor homolog 1 (Drosophila)
  • Fat2: FAT tumor suppressor homolog 2 (Drosophila)
  • Fat3: FAT tumor suppressor homolog 3 (Drosophila)
  • Fbn1: fibrillin 1
  • Fdps: farnesyl diphosphate synthase
  • Fgfr1op2: FGFR1 oncogene partner 2
  • Filip1: filamin A interacting protein 1
  • Fkbp1b: FK506 binding protein 1B, 12.6 kDa
  • Flg: filaggrin
  • Flot1: flotillin 1
  • Flot2: flotillin 2
  • Fosl1: FOS-like antigen 1
  • Fosl2: FOS-like antigen 2
  • Fpgt: fucose-1-phosphate guanylyltransferase
  • Frap1: mechanistic target of rapamycin (serine/threonine kinase)
  • Freq: frequenin homolog (Drosophila)
  • Fyn: FYN oncogene related to SRC, FGR, YES
  • Gaa: glucosidase, alpha; acid
  • Gabbr1: gamma-aminobutyric acid (GABA) B receptor, 1
  • Gabra3: gamma-aminobutyric acid (GABA) A receptor, alpha 3
  • Gabre: gamma-aminobutyric acid (GABA) A receptor, epsilon
  • Gadd45a: growth arrest and DNA-damage-inducible, alpha
  • Galc: galactosylceramidase
  • Galk1: galactokinase 1
  • Galnt10: UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 10
  • Gars: glycyl-tRNA synthetase
  • Gas7: growth arrest-specific 7
  • Gc: group-specific component (vitamin D binding protein)
  • Gdi1: GDP dissociation inhibitor 1
  • Gdi2: GDP dissociation inhibitor 2
  • Gfap: glial fibrillary acidic protein
  • Gif: gastric intrinsic factor (vitamin B synthesis)
  • Gjb2: gap junction protein, beta 2, 26 kDa
  • Gla: galactosidase, alpha
  • Gldc: glycine dehydrogenase (decarboxylating)
  • Glra2: glycine receptor, alpha 2
  • Glut3: solute carrier family 2 (facilitated glucose transporter), member 3
  • Gmcl1: germ cell-less homolog 1 (Drosophila)
  • Gmfb: glia maturation factor, beta
  • Gna11: guanine nucleotide binding protein (G protein), alpha 11 (Gq class)
  • Gnai1: guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1
  • Gnai2: guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2
  • Gnao1: guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O
  • Gnaq: guanine nucleotide binding protein (G protein), q polypeptide
  • Gnaz: guanine nucleotide binding protein (G protein), alpha z polypeptide
  • Gnb2l1: guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1
  • Gnl3: guanine nucleotide binding protein-like 3 (nucleolar)
  • Gnpat: glyceronephosphate O-acyltransferase
  • Gpi: glucose phosphate isomerase
  • Gpm6a: glycoprotein M6A
  • Gpr1: G protein-coupled receptor 1
  • Gpr141: G protein-coupled receptor 141
  • Gpr56: G protein-coupled receptor 56
  • Gpsm1: G-protein signaling modulator 1 (AGS3-like, C. elegans)
  • Gpt2: glutamic pyruvate transaminase (alanine aminotransferase) 2
  • Grin1: glutamate receptor, ionotropic, N-methyl D-aspartate 1
  • Grpel1: GrpE-like 1, mitochondrial (E. coli)
  • Gstm2: glutathione S-transferase mu 2 (muscle)
  • Gstm3: glutathione S-transferase mu 3 (brain)
  • Gucy2d: guanylate cyclase 2D, membrane (retina-specific)
  • Gucy2f: guanylate cyclase 2F, retinal
  • H1f0: H1 histone family, member 0
  • H1f4: histone cluster 1, H1e
  • H2afy: H2A histone family, member Y
  • Haao: 3-hydroxyanthranilate 3,4-dioxygenase
  • Hap1: huntingtin-associated protein 1
  • Hapln3: hyaluronan and proteoglycan link protein 3
  • Hbld2: iron-sulfur cluster assembly 1 homolog (S. cerevisiae)
  • Hck: hemopoietic cell kinase
  • Hcn1: hyperpolarization activated cyclic nucleotide-gated potassium channel 1
  • Hdac6: histone deacetylase 6
  • Hdgf: hepatoma-derived growth factor (high-mobility group protein 1-like)
  • Hdlbp: high density lipoprotein binding protein
  • Hey1: hairy/enhancer-of-split related with YRPW motif 1
  • Hgf: hepatocyte growth factor (hepapoietin A; scatter factor)
  • Hip1r: huntingtin interacting protein 1 related
  • Hivep1: human immunodeficiency virus type I enhancer binding protein 1
  • Hk1: hexokinase 1
  • Hmga2: high mobility group AT-hook 2
  • Hmgcr: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase
  • Hmgcs1: 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)
  • Hmgn3: high mobility group nucleosomal binding domain 3
  • Hn1: hematological and neurological expressed 1
  • Hnf4a: hepatocyte nuclear factor 4, alpha
  • Hnmt: histamine N-methyltransferase
  • Hnrnph1: heterogeneous nuclear ribonucleoprotein H1 (H)
  • Hnrpa1: heterogeneous nuclear ribonucleoprotein A1
  • Hnrpk: heterogeneous nuclear ribonucleoprotein K
  • Hnrpu: heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A)
  • hook3: hook homolog 3 (Drosophila)
  • Hps5: Hermansky-Pudlak syndrome 5
  • Hpse: heparanase
  • Hras1: v-Ha-ras Harvey rat sarcoma viral oncogene homolog
  • Hsd11b2: hydroxysteroid (11-beta) dehydrogenase 2
  • Hsd17B1: hydroxysteroid (17-beta) dehydrogenase 1
  • Hsf1: heat shock transcription factor 1
  • Hsp90ab1: heat shock protein 90 kDa alpha (cytosolic), class B member 1
  • Hspa14: heat shock 70 kDa protein 14
  • Hspe1: heat shock 10 kDa protein 1 (chaperonin 10)
  • Htr2c: 5-hydroxytryptamine (serotonin) receptor 2C
  • Htr3a: 5-hydroxytryptamine (serotonin) receptor 3A
  • Htr4: 5-hydroxytryptamine (serotonin) receptor 4
  • Hyou1: hypoxia up-regulated 1
  • Id2: inhibitor of DNA binding 2, dominant negative helix-loop-helix protein
  • Idh1: isocitrate dehydrogenase 1 (NADP+), soluble
  • Igf1r: insulin-like growth factor 1 receptor
  • Igf2r: insulin-like growth factor 2 receptor
  • Ikbkap: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein
  • IL1b: interleukin 1, beta
  • Il1r2: interleukin 1 receptor, type II
  • Il1rapl1: interleukin 1 receptor accessory protein-like 1
  • Il6: interleukin 6 (interferon, beta 2)
  • Ilf3: interleukin enhancer binding factor 3, 90 kDa
  • Inhbc: inhibin, beta C
  • Inpp4a: inositol polyphosphate-4-phosphatase, type I, 107 kDa
  • Inpp4b: inositol polyphosphate-4-phosphatase, type II, 105 kDa
  • Inpp5d: inositol polyphosphate-5-phosphatase, 145 kDa
  • Irs1: insulin receptor substrate 1
  • Irs2: insulin receptor substrate 2
  • Isg20: interferon stimulated exonuclease gene 20 kDa
  • Itga6: integrin, alpha 6
  • Itm2c: integral membrane protein 2C
  • Itpr2: inositol 1,4,5-triphosphate receptor, type 2
  • Itpr3: inositol 1,4,5-triphosphate receptor, type 3
  • Ivl: involucrin
  • Jag1: jagged 1 (Alagille syndrome)
  • Jak1: Janus kinase 1
  • Jak2: Janus kinase 2
  • Junb: jun B proto-oncogene
  • Kalrn: kalirin, RhoGEF kinase
  • Katna1: katanin p60 (ATPase-containing) subunit A 1
  • Kcnh1: potassium voltage-gated channel, subfamily H (eag-related), member 1
  • Kcnh2: potassium voltage-gated channel, subfamily H (eag-related), member 2
  • Kcnk2: potassium channel, subfamily K, member 2
  • Kcns1: potassium voltage-gated channel, delayed-rectifier, subfamily S, member 1
  • Kcns3: potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3
  • Kcnt1: potassium channel, subfamily T, member 1
  • Kif5a: kinesin family member 5A
  • Klc1: kinesin light chain 1
  • Klhl12: kelch-like 12 (Drosophila)
  • Kpnb1: karyopherin (importin) beta 1
  • Kras: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
  • Lama5: laminin, alpha 5
  • Lancl1: LanC lantibiotic synthetase component C-like 1 (bacterial)
  • Lars: leucyl-tRNA synthetase
  • Lbp: lipopolysaccharide binding protein
  • Lcmt1: leucine carboxyl methyltransferase 1
  • Letm1: leucine zipper-EF-hand containing transmembrane protein 1
  • Lgi1: leucine-rich, glioma inactivated 1
  • Lgr7: relaxin/insulin-like family peptide receptor 1
  • Lhfpl4: lipoma HMGIC fusion partner-like 4
  • Lhx3: LIM homeobox 3
  • Lifr: leukemia inhibitory factor receptor alpha
  • Lin10: chromosome 16 open reading frame 70
  • LMO7: LIM domain 7
  • Lphn1: latrophilin 1
  • Lphn2: latrophilin 2
  • Lpin1: lipin 1
  • Lrpap1: low density lipoprotein receptor-related protein associated protein 1
  • Lsamp: limbic system-associated membrane protein
  • Ltbp1: latent transforming growth factor beta binding protein 1
  • Luzp1: leucine zipper protein 1
  • Ly6g5b: lymphocyte antigen 6 complex, locus G5B
  • Lyar: Ly1 antibody reactive homolog (mouse)
  • LYL1: lymphoblastic leukemia derived sequence 1
  • Lyst: lysosomal trafficking regulator
  • Lzic: leucine zipper and CTNNBIP1 domain containing
  • M6pr: mannose-6-phosphate receptor (cation dependent)
  • Magi3: membrane associated guanylate kinase, WW and PDZ domain containing 3
  • Maoa: monoamine oxidase A
  • Map1lc3a: microtubule-associated protein 1 light chain 3 alpha
  • Map2: microtubule-associated protein 2
  • Map3k7ip2: mitogen-activated protein kinase kinase kinase 7 interacting protein 2
  • Map4: microtubule-associated protein 4
  • Mapk1: mitogen-activated protein kinase 1
  • Mapkapk2: mitogen-activated protein kinase-activated protein kinase 2
  • Mark1: MAP/microtubule affinity-regulating kinase 1
  • Mark3: MAP/microtubule affinity-regulating kinase 3
  • Matr3: matrin 3
  • Mcm7: minichromosome maintenance complex component 7
  • Mdga2: MAM domain containing glycosylphosphatidylinositol anchor 2
  • Mdh1: malate dehydrogenase 1, NAD (soluble)
  • Mecp2: methyl CpG binding protein 2 (Rett syndrome)
  • Mfap3: microfibrillar-associated protein 3
  • Mgat1: mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
  • Mgat5: mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase
  • Mid1: midline 1 (Opitz/BBB syndrome)
  • Mkln1: muskelin 1, intracellular mediator containing kelch motifs
  • Mkrn2: makorin ring finger protein 2
  • Mlp: MARCKS-like 1
  • Mmp10: matrix metallopeptidase 10 (stromelysin 2)
  • Mnat1: ménage à trois homolog 1, cyclin H assembly factor (Xenopus laevis)
  • Mpdz: multiple PDZ domain protein
  • Mpi: mannose phosphate isomerase
  • Mpo: myeloperoxidase
  • mpp7: membrane protein, palmitoylated 7 (MAGUK p55 subfamily member 7)
  • mre11: MRE11 meiotic recombination 11 homolog A (S. cerevisiae)
  • Mrpl38: mitochondrial ribosomal protein L38
  • Mrpl9: mitochondrial ribosomal protein L9
  • Mrps9: mitochondrial ribosomal protein S9
  • Msn: moesin
  • Mtap: methylthioadenosine phosphorylase
  • Mtdh: metadherin
  • Mtmr3: myotubularin-related protein 3
  • Mtr: 5-methyltetrahydrofolate-homocysteine methyltransferase
  • Mtus1: microtubule-associated tumor suppressor 1
  • Mx1: myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)
  • Mybpc1: myosin binding protein C, slow type
  • myc: v-myc myelocytomatosis viral oncogene homolog (avian)
  • Mycbpap: MYCBP associated protein
  • Myh10: myosin, heavy chain 10, nonmuscle
  • Myh6: myosin, heavy chain 6, cardiac muscle, alpha
  • Myh9: myosin, heavy chain 9, nonmuscle
  • Myo1a: myosin IA
  • Myo1e: myosin IE
  • Myo5a: myosin VA (heavy chain 12, myoxin)
  • Myo5b: myosin VB
  • Myo7a: myosin VIIA
  • Myo9a: myosin IXA
  • Myom1: myomesin 1, 185 kDa
  • Nab1: NGFI-A binding protein 1 (EGR1 binding protein 1)
  • Nab2: NGFI-A binding protein 2 (EGR1 binding protein 2)
  • Naca: nascent polypeptide-associated complex alpha subunit
  • Naglu: N-acetylglucosaminidase, alpha-
  • Nap1l3: nucleosome assembly protein 1-like 3
  • Napepld: N-acyl phosphatidylethanolamine phospholipase D
  • Nasp: nuclear autoantigenic sperm protein (histone-binding)
  • Ncam1: neural cell adhesion molecule 1
  • Ncam2: neural cell adhesion molecule 2
  • Ncdn: neurochondrin
  • Ncl: nucleolin
  • Ncstn: nicastrin
  • Ndel1: nudE nuclear distribution gene E homolog (A. nidulans)-like 1
  • Ndufa9: NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39 kDa
  • Ndufc2: NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5 kDa
  • Ndufs1: NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75 kDa (NADH-coenzyme Q reductase)
  • Ndufs6: NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13 kDa (NADH-coenzyme Q reductase)
  • Ndufs7: NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20 kDa (NADH-coenzyme Q reductase)
  • Nedd4: neural precursor cell expressed, developmentally down-regulated 4
  • Nef3: neurofilament, medium polypeptide
  • Nefh: neurofilament, heavy polypeptide
  • Negr1: neuronal growth regulator 1
  • Nell1: NEL-like 1 (chicken)
  • Neo1: neogenin homolog 1 (chicken)
  • Nes: nestin
  • Nexn: nexilin (F actin binding protein)
  • Nf2: neurofibromin 2 (merlin)
  • Nfix: nuclear factor I/X (CCAAT-binding transcription factor)
  • Nfkb1: nuclear factor of kappa light polypeptide gene enhancer in B-cells 1
  • Ninj1: ninjurin 1
  • Nlgn2: neuroligin 2
  • Nlgn3: neuroligin 3
  • Nme2: non-metastatic cells 2, protein (NM23B) expressed in
  • Nolc1: nucleolar and coiled-body phosphoprotein 1
  • Nos1: nitric oxide synthase 1 (neuronal)
  • Nos3: nitric oxide synthase 3 (endothelial cell)
  • Notch1: Notch homolog 1, translocation-associated (Drosophila)
  • Notch2: Notch homolog 2 (Drosophila)
  • Notch4: Notch homolog 4 (Drosophila)
  • Npc2: Niemann-Pick disease, type C2
  • Npdc1: neural proliferation, differentiation and control, 1
  • Npepps: aminopeptidase puromycin sensitive
  • Npm1: nucleophosmin (nucleolar phosphoprotein B23, numatrin)
  • Npr2: natriuretic peptide receptor B/guanylate cyclase B (atrionatriuretic peptide receptor B)
  • Npvf: neuropeptide VF precursor
  • Npy5r: neuropeptide Y receptor Y5
  • Nr1i2: nuclear receptor subfamily 1, group I, member 2
  • Nr5a2: nuclear receptor subfamily 5, group A, member 2
  • Nr6a1: nuclear receptor subfamily 6, group A, member 1
  • Nras: neuroblastoma RAS viral (v-ras) oncogene homolog
  • Nrbf2: nuclear receptor binding factor 2
  • Nrp2: neuropilin 2
  • Nsf: N-ethylmaleimide-sensitive factor
  • Ntrk2: neurotrophic tyrosine kinase, receptor, type 2
  • Nucb1: nucleobindin 1
  • Nucb2: nucleobindin 2
  • Nudc: nuclear distribution gene C homolog (A. nidulans)
  • Nup88: nucleoporin 88 kDa
  • Oas3: 2'-5'-oligoadenylate synthetase 3, 100 kDa
  • Obscn: obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF
  • Ociad1: OCIA domain containing 1
  • Odc1: ornithine decarboxylase 1
  • Odf2: outer dense fiber of sperm tails 2
  • Ogfr: opioid growth factor receptor
  • Olfm2: olfactomedin 2
  • Olfm3: olfactomedin 3
  • Omg: oligodendrocyte myelin glycoprotein
  • Optn: optineurin
  • Osbp: oxysterol binding protein
  • Oxr1: oxidation resistance 1
  • P4hb: prolyl 4-hydroxylase, beta polypeptide
  • Pabpc1: poly(A) binding protein, cytoplasmic 1
  • Pabpc4: poly(A) binding protein, cytoplasmic 4 (inducible form)
  • Padi2: peptidyl arginine deiminase, type II
  • Pak3: p21 protein (Cdc42/Rac)-activated kinase 3
  • Palm: paralemmin
  • Panx1: pannexin 1
  • Pard3: par-3 partitioning defective 3 homolog (C. elegans)
  • Parg: poly (ADP-ribose) glycohydrolase
  • Park7: Parkinson disease (autosomal recessive, early onset) 7
  • Pbp: phosphatidylethanolamine binding protein 1
  • Pcca: propionyl Coenzyme A carboxylase, alpha polypeptide
  • Pcdh21: protocadherin 21
  • Pcdha3: protocadherin alpha 3
  • Pcdhb1: protocadherin beta 1
  • Pcdhb10: protocadherin beta 10
  • Pcdhga12: protocadherin gamma subfamily A, 12
  • Pclo: piccolo (presynaptic cytomatrix protein)
  • Pcolce: procollagen C-endopeptidase enhancer
  • Pcsk1n: proprotein convertase subtilisin/kexin type 1 inhibitor
  • Pcsk5: proprotein convertase subtilisin/kexin type 5
  • Pcyox1: prenylcysteine oxidase 1
  • Pdap1: PDGFA associated protein 1
  • Pdcd4: programmed cell death 4 (neoplastic transformation inhibitor)
  • Pdcl: phosducin-like
  • Pde10a: phosphodiesterase 10A
  • Pde4b: phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce homolog, Drosophila)
  • Pdlim7: PDZ and LIM domain 7 (enigma)
  • Pea15: phosphoprotein enriched in astrocytes 15
  • Pecr: peroxisomal trans-2-enoyl-CoA reductase
  • Per1: period homolog 1 (Drosophila)
  • Per3: period homolog 3 (Drosophila)
  • Pfkl: phosphofructokinase, liver
  • PGAP1: post-GPI attachment to proteins 1
  • Phactr3: phosphatase and actin regulator 3
  • Phb: prohibitin
  • Phka1: phosphorylase kinase, alpha 1 (muscle)
  • Phkg2: phosphorylase kinase, gamma 2 (testis)
  • Pi4ka: phosphatidylinositol 4-kinase, catalytic, alpha
  • Picalm: phosphatidylinositol binding clathrin assembly protein
  • Pik3c3: phosphoinositide-3-kinase, class 3
  • Pik3cb: phosphoinositide-3-kinase, catalytic, beta polypeptide
  • Pik3r2: phosphoinositide-3-kinase, regulatory subunit 2 (beta)
  • Pim1: pim-1 oncogene
  • Pip5k2a: phosphatidylinositol-5-phosphate 4-kinase, type II, alpha
  • Pitpnm1: phosphatidylinositol transfer protein, membrane-associated 1
  • Pkia: protein kinase (cAMP-dependent, catalytic) inhibitor alpha
  • Pkm2: pyruvate kinase, muscle
  • Pla2g2a: phospholipase A2, group IIA (platelets, synovial fluid)
  • Plb1: phospholipase B1
  • Plcb4: phospholipase C, beta 4
  • Plcd4: phospholipase C, delta 4
  • Plec1: plectin 1, intermediate filament binding protein 500kDa
  • Plk1: polo-like kinase 1 (Drosophila)
  • Pnkp: polynucleotide kinase 3'-phosphatase
  • Pnma1: paraneoplastic antigen MA1
  • Ppara: peroxisome proliferator-activated receptor alpha
  • Ppargc1b: peroxisome proliferator-activated receptor gamma, coactivator 1 beta
  • ppfibp2: PTPRF interacting protein, binding protein 2 (liprin beta 2)
  • Ppia: peptidylprolyl isomerase A (cyclophilin A)
  • Ppm2c: pyruvate dehydrogenase phosphatase catalytic subunit 1
  • Ppp1r14b: protein phosphatase 1, regulatory (inhibitor) subunit 14B
  • Ppp1r1a: protein phosphatase 1, regulatory (inhibitor) subunit 1A
  • Ppp1r9a: protein phosphatase 1, regulatory (inhibitor) subunit 9A
  • Ppp2r1a: protein phosphatase 2 (formerly 2A), regulatory subunit A, alpha isoform
  • Ppp3cc: protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform
  • Pqlc1: PQ loop repeat containing 1
  • Prdx1: peroxiredoxin 1
  • Prdx6: peroxiredoxin 6
  • Prg3: proteoglycan 3
  • Prkaa2: protein kinase, AMP-activated, alpha 2 catalytic subunit
  • Prkaca: protein kinase, cAMP-dependent, catalytic, alpha
  • Prkar1a: protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)
  • Prkar2a: protein kinase, cAMP-dependent, regulatory, type II, alpha
  • Prkcd: protein kinase C, delta
  • PRKCQ: protein kinase C, theta
  • Prkwnk1: WNK lysine deficient protein kinase 1
  • Prlh: prolactin releasing hormone
  • Prmt3: protein arginine methyltransferase 3
  • Prpsap2: phosphoribosyl pyrophosphate synthetase-associated protein 2
  • Prrx2: paired related homeobox 2
  • Prss12: protease, serine, 12 (neurotrypsin, motopsin)
  • Prss15: lon peptidase 1, mitochondrial
  • Prx: periaxin
  • Psap: prosaposin
  • Pscd2: cytohesin 2
  • Pscd3: cytohesin 3
  • Psg4: pregnancy specific beta-1-glycoprotein 4
  • Psma1: proteasome (prosome, macropain) subunit, alpha type, 1
  • Psma2: proteasome (prosome, macropain) subunit, alpha type, 2
  • Psmc4: proteasome (prosome, macropain) 26S subunit, ATPase, 4
  • Psme2: proteasome (prosome, macropain) activator subunit 2 (PA28 beta)
  • Ptbp1: polypyrimidine tract binding protein 1
  • Ptch1: patched homolog 1 (Drosophila)
  • Pth: parathyroid hormone
  • Pthr2: parathyroid hormone 2 receptor
  • Ptk2b: PTK2B protein tyrosine kinase 2 beta
  • Ptp4a1: protein tyrosine phosphatase type IVA, member 1
  • Ptpn11: protein tyrosine phosphatase, non-receptor type 11
  • Ptpn23: protein tyrosine phosphatase, non-receptor type 23
  • Ptprj: protein tyrosine phosphatase, receptor type, J
  • Ptprr: protein tyrosine phosphatase, receptor type, R
  • Ptprv: protein tyrosine phosphatase, receptor type, V (pseudogene)
  • Pxn: paxillin
  • Pygl: phosphorylase, glycogen, liver
  • Qscn6: quiescin Q6 sulfhydryl oxidase 1
  • Rab10: RAB10, member RAS oncogene family
  • Rab14: RAB14, member RAS oncogene family
  • Rab2: RAB2A, member RAS oncogene family
  • Rab21: RAB21, member RAS oncogene family
  • Rab35: RAB35, member RAS oncogene family
  • Rab3il1: RAB3A interacting protein (rabin3)-like 1
  • Rab4a: RAB4A, member RAS oncogene family
  • Rab5a: RAB5A, member RAS oncogene family
  • Rab7: RAB7A, member RAS oncogene family
  • Rab9: RAB9A, member RAS oncogene family
  • Rabac1: Rab acceptor 1 (prenylated)
  • Rabggta: Rab geranylgeranyltransferase, alpha subunit
  • Rac1: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)
  • Rala: v-ral simian leukemia viral oncogene homolog A (ras related)
  • RalB: v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)
  • Ralb: v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)
  • Raly: RNA binding protein, autoantigenic (hnRNP associated with lethal yellow homolog (mouse))
  • RanGap1: Ran GTPase activating protein 1
  • Rap2b: RAP2B, member of RAS oncogene family
  • Rbbp6: retinoblastoma binding protein 6
  • Rbl2: retinoblastoma-like 2 (p130)
  • Rbm3: RNA binding motif (RNP1, RRM) protein 3
  • Rcn1: reticulocalbin 1, EF-hand calcium binding domain
  • Rcvrn: recoverin
  • Rdh10: retinol dehydrogenase 10 (all-trans)
  • Rdx: radixin
  • Rest: RE1-silencing transcription factor
  • Rgs4: regulator of G-protein signaling 4
  • Rgs5: regulator of G-protein signaling 5
  • Rgs7: regulator of G-protein signaling 7
  • Rhoa: ras homolog gene family, member A
  • RhoB: ras homolog gene family, member B
  • Rhoj: ras homolog gene family, member J
  • Rims1: regulating synaptic membrane exocytosis 1
  • Rnasel: ribonuclease L (2',5'-oligoisoadenylate synthetase-dependent)
  • Rnf36: tripartite motif-containing 69
  • Rnf40: ring finger protein 40
  • Robo1: roundabout, axon guidance receptor, homolog 1 (Drosophila)
  • Robo4: roundabout homolog 4, magic roundabout (Drosophila)
  • Rock1: Rho-associated, coiled-coil containing protein kinase 1
  • Rock2: Rho-associated, coiled-coil containing protein kinase 2
  • rora: RAR-related orphan receptor A
  • Rpe65: retinal pigment epithelium-specific protein 65 kDa
  • Rpl13: ribosomal protein L13
  • Rpl6: ribosomal protein L6
  • Rplp1: ribosomal protein, large, P1
  • Rpn2: ribophorin II
  • Rps15: ribosomal protein S15
  • Rps16: ribosomal protein S16
  • Rps6ka2: ribosomal protein S6 kinase, 90 kDa, polypeptide 2
  • Rtcd1: RNA terminal phosphate cyclase domain 1
  • Rtkn: rhotekin
  • Rtn1: reticulon 1
  • Rtn3: reticulon 3
  • Rtn4: reticulon 4
  • Rtn4r: reticulon 4 receptor
  • Samsn1: SAM domain, SH3 domain and nuclear localization signals 1
  • Sardh: sarcosine dehydrogenase
  • Sart1: squamous cell carcinoma antigen recognized by T cells
  • Sbds: Shwachman-Bodian-Diamond syndrome
  • Sc4mol: sterol-C4-methyl oxidase-like
  • Sca10: ataxin 10
  • Scg2: secretogranin II (chromogranin C)
  • Scg3: secretogranin III
  • Scn1a: sodium channel, voltage-gated, type I, alpha subunit
  • Scn2a1: sodium channel, voltage-gated, type II, alpha subunit
  • Scn5a: sodium channel, voltage-gated, type V, alpha subunit
  • Scn8a: sodium channel, voltage gated, type VIII, alpha subunit
  • Scoc: short coiled-coil protein
  • Scp2: sterol carrier protein 2
  • SCYB11: chemokine (C-X-C motif) ligand 11
  • Scye1: aminoacyl tRNA synthetase complex-interacting multifunctional protein 1
  • Sdfr1: neuroplastin
  • Sdpr: serum deprivation response
  • SH3gl1: SH3-domain GRB2-like 1
  • SH3glb1: SH3-domain GRB2-like endophilin B1
  • Shank1: SH3 and multiple ankyrin repeat domains 1
  • Sirpa: signal-regulatory protein alpha
  • Skiv2l2: superkiller viralicidic activity 2-like 2 (S. cerevisiae)
  • Slc12a2: solute carrier family 12 (sodium/potassium/chloride transporters), member 2
  • Slc12a9: solute carrier family 12 (potassium/chloride transporters), member 9
  • Slc13a3: solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 3
  • Slc17a6: solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6
  • Slc1a1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1
  • Slc26a4: solute carrier family 26, member 4
  • Slc27a5: solute carrier family 27 (fatty acid transporter), member 5
  • Slc30a1: solute carrier family 30 (zinc transporter), member 1
  • Slc44a4: solute carrier family 44, member 4
  • Slc5a1: solute carrier family 5 (sodium/glucose cotransporter), member 1
  • Slc6a8: solute carrier family 6 (neurotransmitter transporter, creatine), member 8
  • Slc8a1: solute carrier family 8 (sodium/calcium exchanger), member 1
  • Smad4: SMAD family member 4
  • Smc1l1: structural maintenance of chromosomes 1A
  • Smoc1: SPARC related modular calcium binding 1
  • Snai2: snail homolog 2 (Drosophila)
  • Snap25: synaptosomal-associated protein, 25 kDa
  • Snap91: synaptosomal-associated protein, 91 kDa homolog (mouse)
  • Snca: synuclein, alpha (non A4 component of amyloid precursor)
  • Sncb: synuclein, beta
  • Snx3: sorting nexin 3
  • Snx7: sorting nexin 7
  • sod1: superoxide dismutase 1, soluble
  • Sod2: superoxide dismutase 2, mitochondrial
  • Son: SON DNA binding protein
  • Sord: sorbitol dehydrogenase
  • Sox5: SRY (sex determining region Y)-box 5
  • Sp4: Sp4 transcription factor
  • Sp7: Sp7 transcription factor
  • Sqle: squalene epoxidase
  • Srfbp1: serum response factor binding protein 1
  • Sst: somatostatin
  • St6gal2: ST6 beta-galactosamide alpha-2,6-sialyltransferase 2
  • St7l: suppression of tumorigenicity 7 like
  • Stard3nl: STARD3 N-terminal like
  • Stat3: signal transducer and activator of transcription 3 (acute-phase response factor)
  • Stat5a: signal transducer and activator of transcription 5A
  • Stip1: stress-induced-phosphoprotein 1
  • Stk2: NIMA (never in mitosis gene a)-related kinase 4
  • Stk22a: testis-specific serine kinase 1A pseudogene
  • Stmn1: stathmin 1
  • Stmn2: stathmin-like 2
  • Stmn4: stathmin-like 4
  • Strbp: spermatid perinuclear RNA binding protein
  • Stx1a: syntaxin 1A (brain)
  • Stx1b2: syntaxin 1B
  • Stx5: syntaxin 5
  • stxbp1: syntaxin binding protein 1
  • Stxbp3: syntaxin binding protein 3
  • Sulf1: sulfatase 1
  • Svop: SV2 related protein homolog (rat)
  • SYAP1: synapse associated protein 1, SAP47 homolog (Drosophila)
  • Sycp1: synaptonemal complex protein 1
  • Sycp2: synaptonemal complex protein 2
  • Synj2: synaptojanin 2
  • Syt3: synaptotagmin III
  • Syt4: synaptotagmin IV
  • Tacc2: transforming, acidic coiled-coil containing protein 2
  • Tacc3: transforming, acidic coiled-coil containing protein 3
  • Tbx2: T-box 2
  • Tceb3: transcription elongation factor B (SIII), polypeptide 3 (110 kDa, elongin A)
  • Tcp1: t-complex 1
  • Tcp11: t-complex 11 homolog (mouse)
  • Tdg: thymine-DNA glycosylase
  • Tdrd7: tudor domain containing 7
  • Tesk2: testis-specific kinase 2
  • Tfrc: transferrin receptor (p90, CD71)
  • Tgfb1: transforming growth factor, beta 1
  • Thrap3: thyroid hormone receptor associated protein 3
  • Thrb: thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian)
  • Thy1: Thy-1 cell surface antigen
  • Tinag: tubulointerstitial nephritis antigen
  • Tkt: transketolase
  • Tle3: transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila)
  • Tlr5: toll-like receptor 5
  • Tm4sf8: tetraspanin 3
  • Tm9sf2: transmembrane 9 superfamily member 2
  • Tmeff1: transmembrane protein with EGF-like and two follistatin-like domains 1
  • Tmem17: transmembrane protein 17
  • Tmlhe: trimethyllysine hydroxylase, epsilon
  • Tmod2: tropomodulin 2 (neuronal)
  • Tmpo: thymopoietin
  • Tnfrsf14: tumor necrosis factor receptor superfamily, member 14 (herpesvirus entry mediator)
  • Top1: topoisomerase (DNA) I
  • Tpd52l2: tumor protein D52-like 2
  • Tpm4: tropomyosin 4
  • Tra1: heat shock protein 90kDa beta (Grp94), member 1
  • Traf4: TNF receptor-associated factor 4
  • Trib3: tribbles homolog 3 (Drosophila)
  • Trim10: tripartite motif-containing 10
  • Trim25: tripartite motif-containing 25
  • Trim50: tripartite motif-containing 50
  • Trpa1: transient receptor potential cation channel, subfamily A, member 1
  • TrpV6: transient receptor potential cation channel, subfamily V, member 6
  • Tsc1: tuberous sclerosis 1
  • Tsga10: testis specific, 10
  • Tshr: thyroid stimulating hormone receptor
  • Ttc1: tetratricopeptide repeat domain 1
  • Ttn: titin
  • Tub: tubby homolog (mouse)
  • Tubb: tubulin, beta
  • Tubb2: tubulin, beta 2A
  • Txn: thioredoxin
  • U2af2: U2 small nuclear RNA auxiliary factor 2
  • Ubc: ubiquitin C
  • Ube2l3: ubiquitin-conjugating enzyme E2L 3
  • Ubqln1: ubiquilin 1
  • Uchl1: ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
  • Ugcgl1: UDP-glucose glycoprotein glucosyltransferase 1
  • Uhrf1: ubiquitin-like with PHD and ring finger domains 1
  • Unc13: unc-13 homolog B (C. elegans)
  • Unc13a: unc-13 homolog A (C. elegans)
  • Unc13d: unc-13 homolog D (C. elegans)
  • Uqcrfs1: ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1
  • Usp14: ubiquitin specific peptidase 14 (tRNA-guanine transglycosylase)
  • Usp15: ubiquitin specific peptidase 15
  • Vamp2: vesicle-associated membrane protein 2 (synaptobrevin 2)
  • Vangl2: vang-like 2 (van gogh, Drosophila)
  • Vapa: VAMP (vesicle-associated membrane protein)-associated protein A, 33 kDa
  • Vapb: VAMP (vesicle-associated membrane protein)-associated protein B and C
  • Vav1: vav 1 guanine nucleotide exchange factor
  • Vcp: valosin-containing protein
  • Vdac2: voltage-dependent anion channel 2
  • Vegfa: vascular endothelial growth factor A
  • Vgf: VGF nerve growth factor inducible
  • Viaat: solute carrier family 32 (GABA vesicular transporter), member 1
  • Vim: vimentin
  • Vldlr: very low density lipoprotein receptor
  • Vps4a: vacuolar protein sorting 4 homolog A (S. cerevisiae)
  • Vps52: vacuolar protein sorting 52 homolog (S. cerevisiae)
  • Vps54: vacuolar protein sorting 54 homolog (S. cerevisiae)
  • Vsnl1: visinin-like 1
  • Vti1a: vesicle transport through interaction with t-SNAREs homolog 1A (yeast)
  • Vtn: vitronectin
  • Wbp11: WW domain binding protein 11
  • Wbscr1: eukaryotic translation initiation factor 4H
  • Whsc2: Wolf-Hirschhorn syndrome candidate 2
  • Wif1: WNT inhibitory factor 1
  • Wnk4: WNK lysine deficient protein kinase 4
  • Wrnip1: Werner helicase interacting protein 1
  • Xpo7: exportin 7
  • Xrcc5: X-ray repair complementing defective repair in Chinese hamster cells 5
  • Ybx1: Y box binding protein 1
  • yes1: v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1
  • Ywhah: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide
  • Ywhaq: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide
  • Zbtb7a: zinc finger and BTB domain containing 7A
  • Zeb1: zinc finger E-box binding homeobox 1
  • Zfhx2: zinc finger homeobox 2
  • Zfp57: zinc finger protein 57 homolog (mouse)
  • Zmynd19: zinc finger, MYND-type containing 19
  • Znf219: zinc finger protein 219
  • Znf291: S-phase cyclin A-associated protein in the ER
  • Znf292: zinc finger protein 292
  • Znf382: zinc finger protein 382.

C.

Cellular signaling pathway clusters of extracted proteins from primary cortical tissue. Specific cellular signaling pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

C.1. ERK/MAPK Signaling (Enrichment Ratio*−log  10(p))

Control Protein (1.32502) —

PPP2R2A, CRK, PPP1R14B, DUSP2, PTK2, SHC1, PAK1, PPP1R10, PPP1R7, PIK3CG, STAT1, PRKCA, ETS1, SRC, PAK2, YWHAB, CRKL, PRKAR2A, STAT3, PLA2G4C, FOS, PPP2CB, PPP2R1A, PRKAR2B, PRKCI, PAK3, PPP2R2B, PRKACA, PPP2R5E, ELK1, PPP2R1B, PRKAR1A, PRKCB.

3xTgAD Protein (0.1537) —

PXN, YWHAH, PTK2B, RAC1, PRKAR2A, PLA2G2A, STAT3, MYC, YWHAQ (includes EG:10971), PPP2R1A, PAK3, PIK3C3, PRKCD, PRKACA, PIK3CB, PIK3R2, ELK1, FYN, PRKAR1A.

C.2. Inositol Phosphate Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.86424) —

PDIA3, OCRL, PAK1, PIK3CG, PRKAA2, PLCB1, PLCL1, PI4KA, PMPCA, ATM, GRK4, PRKCQ, PAK2, CDK7, CDK6, PLK1, GRK5, ITPKA, SYNJ2, PIP5K1A, PAK3, SYNJ1, PIP5K1C, GRK6, PIP4K2A, PIP4K2C, CDK2.

3xTgAD Protein (0.15355) —

PLK1, INPP5D, SYNJ2, INPP4A, INPP4B, INPP4B, PAK3, PIM1, PRKCD, PIK3C3, PRKAA2, PIK3CB, PIK3R2, PIP4K2A, PLCD4, PI4KA, ATM.

C.3. Wnt/β-Catenin Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.5609) —

PPP2R2A, SOX10, CSNK1E, WIF1, WNT7A, TGFB1, SMO, CSNK2A1, CSNK2B, CTNNB1, SRC, SFRP4, GJA1, CSNK1G2, DVL1, FZD9, PPP2CB, CDH2, CDH1, PPP2R1A, PPP2R2B, TLE3, PPP2R5E, UBC, PPP2R1B, WNT5A.

3xTgAD Protein (0.12772) —

CSNK1G1, CSNK1G3, DVL1, ACVR1, APC, MYC, CSNK1E, PPP2R1A, CDH2, CDH1, WIF1, TGFB1, GNAO1, TLE3, UBC, CTNNB1, SOX5 (includes EG:6660).

C.4. Calcium Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.33825) —

TRPC2, GRIN2A, TNNI2, GRIA1, RCAN2, CALM2, CHRNB4, TRPC5, TNNT3, RYR3, GRIK1, GRIN2B, PRKAR2A, TRPC4, PPP3CC, TRPC7, CHRNG, PRKAR2B, TPM3, CAMKK1, PRKACA, TNNI1, CHRNB3, CAMKK2, PRKAR1A.

3xTgAD Protein (0.110875) —

RAP2B, MYH10, CALR, MYH6, ATP2B1, PRKAR2A, TPM4, PPP3CC, ATP2B2, HDAC6, TRPV6, HTR3A, CAMKK1, PRKACA, MYH9, SLC8A1, ACTA1, PRKAR1A.

C.5. Tight Junction Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.4147) —

TJP2, CDC42, TJP1, PPP2R2A, CLDN19, VAPA, PRKAR2A, PRKCZ, FOS, PPP2CB, PPP2R1A, PRKCI, PRKAR2B, CLDN4, CLDN1, TGFB1, PPP2R2B, PRKACA, PPP2R5E, STX4, CTNNB1, PPP2R1B, PRKAR1A.

3xTgAD Protein (0.24514) —

MYH10, MYH6, CDC42, ACTB, HSF1, CLDN18, VAPA, RAC1, PRKAR2A, MPDZ, PPP2R1A, TGFB1, RHOA, CEBPA, PRKACA, MYH9, CTNNB1, ACTA1, PRKAR1A.

C.6. NF-κB Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.12096) —

PRKCQ, EGF, PRKCZ, TLR9, TLR4, TLR5, PIK3CG, TLR6, PRKACA, CSNK2A1, PDGFRA, TLR3, CSNK2B, PRKCB, EGFR.

3xTgAD Protein (0.0190128) —

IL1R2, TLR5, BCL10, PIK3C3, PRKACA, IL1B, PIK3CB, PIK3R2, NFKB1, EGFR.

C.7. PTEN Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.1368) —

PTK2, SHC1, CDC42, PIK3CG, CSNK2A1, PDGFRA, CSNK2B, CDKN1B, PRKCZ, FASLG, EGFR.

3xTgAD Protein (0.1199) —

CDC42, YWHAH, RAC1, PIK3CB, PIK3R2, CDKN1B, NFKB1, INPP5D, EGFR, MAGI3.

C.8. SAPK/JNK Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.0544984) —

SHC1, CDC42, GADD45A, CRKL, PIK3CG, CRK, ELK1, GNG7.

3xTgAD Protein (0.0717288) —

CDC42, GADD45A, IRS1, PIK3C3, RAC1, PIK3CB, PIK3R2, ELK1, HNRNPK.

C.9. PI3K/AKT Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.15481) —

TSC1, PPP2R2A, YWHAB, PRKCZ, PPP2CB, SHC1, PPP2R1A, PIK3CG, TSC2, PPP2R2B, PPP2R5E, CDKN1B, CTNNB1, PPP2R1B.

3xTgAD Protein (0.19323) —

TSC1, JAK1, YWHAH, JAK2, NOS3, INPP5D, YWHAQ (includes EG:10971), MTOR, PPP2R1A, HSP90AB1, PIK3CB, PIK3R2, CDKN1B, CTNNB1.

C.10. p38 MAPK Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.0630702) —

IL1R2, MYC, TGFB1, MAP3K7IP2, IL1B, PLA2G2A, EEF2K, MAPKAPK2, ELK1.

C.11. p53 Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.037996) —

GADD45A, FASN, PIK3CG, SNAI2, CTNNB1, CDK2, ATM, SERPINE2.

3xTgAD Protein (0.12075) —

CCND2, GADD45A, PIK3C3, SNAI2, CABC1, PIK3CB, PIK3R2, BAX, CTNNB1, ATM.

C.12. JAK/Stat Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.051714) —

SHC1, SOCS1, PTPN11, PIK3CG, STAT3, STAT1.

3xTgAD Protein (0.25857) —

STAT5A, MTOR, JAK1, PTPN11, PIK3C3, PIK3CB, STAT3, PIK3R2, JAK2.

D.

Neuronal function pathway clusters of extracted proteins from primary cortical tissue. Specific neuronal function pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

D.1. Synaptic Long-Term Potentiation (Enrichment Ratio*−log  10(p))

Control Protein (1.27872) —

GRIN2B, GRIN2A, PRKCQ, PPP1R1A, GRIA1, PRKAR2A, CALM2, CACNA1C, PPP3CC, GRM4, PPP1R14B, PRKCZ, GRM5, PRKCI, PRKAR2B, PPP1R10, PPP1R7, PPP1R14D, PRKACA, PLCB1, PRKD1, PRKCA, PRKAR1A, PRKCB

3xTgAD Protein (0) —

D.2. Axonal Guidance Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.69525) —

NOS1, GUCY1B2, PRKCQ, GUCY1A3, GUCY2D, PPP2R2A, GRID2, GRIA1, GRM4, PRKCZ, GRM5, PPP2CB, PPP2R1A, PRKCI, PPP2R2B, RYR3, GUCY1A2, PLCB1, PPP2R5E, PPP2R1B, PRKD1, PRKCA, PRKCB.

3xTgAD Protein (0.1918) —

NOS1, GUCY2D, GNAI1, PLA2G2A, GNAZ, NOS3, PRDX6, GNAI2, PPP2R1A, PRKCD, GNAO1, IGF1R, GUCY2F, ADCY8, NPR2.

D.3. Synaptic Long-Term Depression (Enrichment Ratio*−log  10(p))

Control Protein (0.47428) —

NOS1, GUCY1B2, PRKCQ, GUCY1A3, GUCY2D, PPP2R2A, GRID2, GRIA1, GRM4, PRKCZ, GRM5, PPP2CB, PPP2R1A, PRKCI, PPP2R2B, RYR3, GUCY1A2, PLCB1, PPP2R5E, PPP2R1B, PRKD1, PRKCA, PRKCB.

3xTgAD Protein (0.11112) —

NOS1, GUCY2D, GNAI1, PLA2G2A, GNAZ, NOS3, PRDX6, GNAI2, PPP2R1A, PRKCD, GNAO1, IGF1R, GUCY2F, ADCY8, NPR2.

D.4. Parkinson's Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.168256) —

UCHL1, PARK7, SNCA.

3xTgAD Protein (0.18656) —

UCHL1, PARK7, SNCA.

D.5. Huntington's Disease Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.20048) —

EGF, GNG7, PRKCZ, TGM2, CTSD, SHC1, PIK3CG, VAMP3, PLCB1, PRKD1, PRKCA, EGFR, SDHA, GRIN2B, PRKCQ, YKT6, SH3GL3, STX1A, SNAP25, TAF9B, GRM5, PRKCI, UBC, GOSR2, SNCA, PRKCB.

3xTgAD Protein (0.36179) —

VTI1A, HSPA14, REST, GNB2L1, HDAC6, NSF, MTOR, PIK3C3, IGF1R, PIK3R2, EGFR, CAPN5, CAPN6, CLTC, BAX, STX1A, SNAP25, DNM1, DNAJC5, ATP5B, CAPN1, PRKCD, HAP1, DCTN1, PIK3CB, UBC, SNCA, CASP7.

D.6. Regulation of Actin-Based Motility by Rho (Enrichment Ratio*−log  10(p))

Control Protein (0.1476) —

PIP5K1A, WIPF1, PAK1, PAK2, CDC42, CFL1, PAK3, PIP5K1C, PIP4K2A, PIP4K2C, PI4KA.

3xTgAD Protein (0.3243) —

CDC42, CFL1, ACTB, RAC1, RHOJ, ROCK1, PAK3, RHOB, RHOA, ARHGDIA, PIP4K2A, ACTA1, PI4KA.

D.7. Amyotrophic Lateral Sclerosis Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.23184) —

NOS1, GRIN2B, GRIN2A, SOD1, GRIA1, PGF, VEGFA, PAK1, GRIK4, PIK3CG, CAT, GLUL, SSR4.

3xTgAD Protein (0.55955) —

NOS1, CAPN5, CAPN6, SOD1, RAB5A, RAC1, NEFH, BAX, CCS, VEGFA, CAPN1, PIK3C3, NEFM, PIK3CB, PIK3R2, CASP7.

D.8. Actin Cytoskeleton Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.0763861) —

PAK2, CFL1, CDC42, CRKL, EGF, CRK, TTN, PTK2, SHC1, PAK1, PIP5K1A, PAK3, PIP5K1C, FGF18, PIK3CG, EZR, FGF23, PIP4K2A, PIP4K2C, GIT1.

3xTgAD Protein (0.44928) —

MYH10, MYH6, CDC42, ROCK2, PIK3C3, EZR, PIK3R2, LBP, ACTA1, PXN, ARHGEF12, CFL1, ACTB, RAC1, RDX, APC, TTN, ROCK1, PAK3, RHOA, ARHGEF6, MYH9, VAV1, PIK3CB, ACTN4, PIP4K2A, MSN.

D.9. Amyloid Processing (Enrichment Ratio*−log  10(p))

Control Protein (0.20636) —

CSNK1E, PRKAR2B, CSNK2A, PRKAR2A, PRKACA, NCSTN, CSNK2B, PRKAR1A.

3xTgAD Protein (0.66144) —

CSNK1E, CAPN5, CAPN6, CAPN1, MARK1, PRKAR2A, PRKACA, NCSTN, BACE1, APP, PRKAR1A.

E.

Energy regulation/Metabolism pathway clusters of extracted proteins from primary cortical tissue. Specific energy regulation/metabolism pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

E.1. Amino Sugars Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.61425) —

FMO3, PDE7A, PDE10A, GM2A, CYB5R1, PDE4A, PDE4B, PDE1A, PDE4D, GFPT2, PDE1C, PDE7B, GALK1, CYB5R3.

3xTgAD Protein (0.0471409) —

HK1, CYB5R4, PDE10A, GALK1, CYB5R3, PDE4B.

E.2. Pentose Phosphate Pathway (Enrichment Ratio*−log  10(p))

Control Protein (0.48608) —

GPI, PGD, TKT, TALDO1, PRPSAP1, PGM1, PRPSAP2, PFKP, PFKL, PDHB, PFKM.

3xTgAD Protein (0.0245154) —

GPI, TKT, PRPSAP2, PFKL.

E.3. Glutamate Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.31165) —

FMO3, GPT, GLUL, GCLC, GLUD1, GOT1, GOT2, GFPT2, EPRS.

3xTgAD Protein (0) —

E.4. Pantothenate and CoA Biosynthesis (Enrichment Ratio*−log  10(p))

Control Protein (0.34188) —

ENPP3, CRMP1, BCAT1, DPYD, DPYSL3, ENPP5, ENPP2.

3xTgAD Protein (0.0348908) —

CRMP1, DPYD, ENPP2.

E.5. Glycolysis/Gluconeogenesis (Enrichment Ratio*−log  10(p))

Control Protein (0.28363) —

PKM2, PGK1, ENO3, ENO2, GAPDH (includes EG:2597), PGM1, ALDH1L1, PFKP, PFKL, PDHB, PFKM, GPI, GALK1, DLAT, PGAM1, DLD.

3xTgAD Protein (0.0610449) —

PKM2, HK1, ADH1A, GPI, ALDH1A3, DLAT, GALK1, ENO2, PFKL, ACSL1.

E.6. Citrate Cycle (Enrichment Ratio*−log  10(p))

Control Protein (0.1581) —

SDHA, PC, CS, SUCLG1, DLD, PCK1.

3xTgAD Protein (0) —

E.7. Galactose Metabolism

Control Protein (0.104958) —

GLA, GALT, GALK1, GAA, PGM1, PFKP, PFKL, PFKM.

3xTgAD Protein (0.0486688) —

HK1, GLA, GALK1, GAA, PFKL, AKR1B1.

E.8. Glycosphingolipid Biosynthesis—Globoseries (Enrichment Ratio*−log  10(p))

Control Protein (0.0411384) —

GLA, ST3GAL1, GM2A.

3xTgAD Protein (0) —

E.9. Glycosphingolipid Biosynthesis—Ganglioseries (Enrichment Ratio*−log  10(p))

Control Protein (0.008832) —

ST3GAL1, GM2A.

3xTgAD Protein (0) —

E.10. N-Glycan Biosynthesis (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.015272) —

RPN2, ST6GAL2, MGAT5, MGAT1.

E.11. Pentose and Glucuronate Interconversions (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.0184464) —

UCHL1, B3GAT1, HPSE, DCXR, AKR1B1.

E.12. Fatty Acid Elongation in Mitochondria (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.0206016) —

ECHS1, PECR.

E.13. Glycerophospholipid Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.0232106) —

GPAM, PCYT1B, PLD3, CDS1, PDIA3, GNPAT, DGKB, DGKG, PLCB1, PLCL1.

3xTgAD Protein (0.048204) —

AGPAT4, CDS1, GNPAT, CHKA, AGPAT1, DGKG, PLA2G2A, CLCF1, PHKA1, PLCD4, PRDX6.

E.14. Fatty Acid Biosynthesis (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.0329256) —

ACACB, ACACA.

E.15. Purine Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.08616) —

ENTPD8, PDE7A, PDE4A, DNTT, PDE1A, PDE4D, PSMC5, PDE7B, VCP, DHX16, ENPP2, PRPSAP2, PKM2, TJP2, GUCY1B2, GUCY1A3, GUCY2D, PDE10A, ENPP5, PDE4B, PDE1C, ENPP3, PSMC1, ENTPD2, PRPSAP1, GUCY1A2, PDE5A, DDX1, GMPR2, PSMC3.

3xTgAD Protein (0.124932) —

MYH6, ENTPD8, NME2, DNTT, WRNIP1, ABCC1, VCP, KATNA1, ATP5H (includes EG:10476), ENPP2, PRPSAP2, ADCY8, ATP5F1, ATP5I, ATP5J, PKM2, ATP1B1, GUCY2D, PDE10A, AMPD1, ATP5A1, AK3, PSMC4, PDE4B, DDX19B, ATP5B, GUCY2F, MYH9, DDX1, NPR2.

E.16. Pyruvate Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.0214935) —

PKM2, PC, DLAT, DLD, PCK1, PDHB, GLO1.

3xTgAD Protein (0.070173) —

PKM2, ACACB, ALDH1A3, DLAT, ACAT1, ACACA, MDH1, AKR1B1, ACSL1.

E.17. Butanoate Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.0523452) —

ECHS1, ALDH1A3, AACS, ACAT1, MYO5B, DCXR, HMGCS1.

E.18. Synthesis and Degradation of Ketone Bodies (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.071505) —

ACAT1, HMGCS1.

F.

Cellular stress/damage pathway clusters of extracted proteins from primary cortical tissue. Specific energy cellular stress/damage pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

F.1. NRF2-mediated Oxidative Stress Response (Enrichment Ratio*−log  10(p))

Control Protein (0.44064) —

PRDX1, PPIB, GCLC, PRKCZ, GSTM2, SOD2, PIK3CG, VCP, DNAJA2, TXN, FKBP5, PRKD1, CBR1, PRKCA, GSTK1, SOD1, PRKCQ, TXNRD1, GSTO1, FOS, PRKCI, ERP29, STIP1, CAT, PRKCB, EPHX1.

3xTgAD Protein (0.23751) —

USP14, SOD1, PRDX1, ACTB, GSTM3 (includes EG:2947), JUNB, DNAJC5, GSTM2, SOD2, ERP29, STIP1, PIK3C3, PRKCD, ABCC1, VCP, PIK3CB, FOSL1, PIK3R2, TXN, EIF2AK3, ACTA1.

F.2. Ceramide Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0.15748) —

CTSD, PPP2CB, FOS, PPP2R1A, PPP2R2A, PIK3CG, PPP2R2B, PPP2R5E, PPP2R1B.

3xTgAD Protein (0) —

F.3. Glutathione Metabolism (Enrichment Ratio*−log  10(p))

Control Protein (0.094285) —

OPLAH, PGD, GSTM2, GGT5, GCLC, GGT1, GSTO1, GSTK1, GGT7.

3xTgAD Protein (0) —

F.4. LPS/IL-1 Mediated Inhibition of RXR Function (Enrichment Ratio*−log  10(p))

Control Protein (0.19071) —

SULT1C2, FMO3, CPT1A, CHST7, ALDH1L1, NR1H3, GSTO1, SULT4A1, GSTM2, NR1I2, SREBF1, SULT1A1, CAT, CPT2, FABP4, XPO1, FABP1, FABP7, SULT1E1, FABP3, GSTK1, TLR4, FABP2.

3xTgAD Protein (0.13872) —

PPARA, GSTM3 (includes EG:2947), ABCA1, IL1R2, ABCC2, SLC27A5, GSTM2, ALDH1A3, NR1I2, CPT2, ACSL4, FABP1, IL1B, NR5A2, CHST10, LBP, ABCC4, HMGCS1, ACSL1, MAOA.

F.5. Fatty Acid Elongation in Mitochondria (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.0206016) —

ECHS1, PECR

F.6. Endoplasmic Reticulum Stress Pathway (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.047841) —

EIF2AK3, CASP7.

F.7. Apoptosis Signaling (Enrichment Ratio*−log  10(p))

Control Protein (0) —

3xTgAD Protein (0.059156) —

ACIN1, ROCK1, CAPN5, CAPN6, CAPN1, BAX, CASP7, PARP1.

F.8. Hypoxia Signaling (Enrichment Ratio*−log  10(p))

Control protein (0) —

3xTgAD Protein (0.111983) —

VEGFA, P4HB, HSP90AB1, UBE2L3, NOS3, UBC, ARNT, ATM.

F.9. PPARα/RXRα Activation (Enrichment Ratio*−log  10(p))

Control Protein (0.0315615) —

PDIA3, PRKAR2A, NR2C2, SHC1, PRKAR2B, TGFB1, FASN, PRKACA, PLCB1, GOT2, PLCL1, PRKCB, PRKCA, PRKAR1A.

3xTgAD Protein (0.14586) —

PPARA, ACVR1, PRKAR2A, CD36, IL6, JAK2, ABCA1, IL1R2, ACADL, HSP90AB1, TGFB1, IRS1, PRKACA, SMAD4, IL1B, ADCY8, PLCD4, PRKAR1A.

G.

Receptor signaling pathway clusters of extracted proteins from primary cortical tissue. Specific receptor signaling pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

G.1. Dopamine Receptor Signaling

Control Protein (0.65824) —

PPP2R2A, PRKAR2A, PPP1R14B, PPP2CB, PPP2R1A, PRKAR2B, PPP1R10, PPP1R14D, PPP1R7, PPP2R2B, PRKACA, FREQ, PPP2R5E, PPP2R1B, PRKAR1A, CALY.

3xTgAD Protein (0.071199) —

PPP2R1A, FREQ, PRKAR2A, PRKACA, ADCY8, CALY, MAOA, PRKAR1A.

G.2. PDGF Signaling

Control Protein (0.73892) —

SRC, CRKL, CRK, STAT3, FOS, SHC1, PIK3CG, CSNK2A1, PDGFRA, CAV1, CSNK2B, ELK1, STAT1, PRKCB, PRKCA.

3xTgAD Protein (0.15738) —

MYC, JAK1, PIK3C3, STAT3, PIK3R2, JAK2, ELK1, INPP5D.

G.3. EGF Signaling

Control Protein (0.7956) —

SHC1, FOS, PIK3CG, CSNK2A1, EGF, CSNK2B, STAT3, STAT1, ELK1, PRKCA, EGFR.

3xTgAD Protein (0.22499) —

JAK1, PIK3C3, PIK3CB, STAT3, PIK3R2, ELK1, EGFR.

G.4. Neuregulin Signaling

Control Protein (0.68068) —

SRC, PRKCQ, CRKL, EGF, CRK, ERBB3, PRKCZ, SHC1, PRKCI, PTPN11, ERBB4, CDKN1B, ELK1, PRKD1, PRKCB, EGFR, PRKCA.

3xTgAD Protein (0.1276) —

MYC, STAT5A, MTOR, PTPN11, HSP90AB1, PRKCD, PIK3R2, CDKN1B, ELK1, EGFR.

G.5. Glutamate Receptor Signaling

Control Protein (0.53342) —

GRM5, GRIN2B, GRIN2A, GRIK4, GRIA1, GRID2, CALM2, GLUL, GRIP1, GRM4, GNG7, GRIK1.

3xTgAD Protein (0) —

G.6. Sonic Hedgehog Signaling

Control Protein (0.73272) —

SHH, CCNB1, PRKAR2B, PRKAR2A, PRKACA, SMO, GLI1, PRKAR1A.

3xTgAD Protein (0.20769) —

ADRBK1, PTCH1, PRKAR2A, PRKACA, PRKAR1A.

G.7. TR/RXR Activation

Control Protein (0.5481) —

UCP2, RCAN2, UCP1, THRA, GRIP1, PFKP, PCK1, KLF9, SREBF1, DIO1, FASN, PIK3CG, STRBP, THRB, FGA, SYT12.

3xTgAD Protein (0.0321142) —

MTOR, PIK3C3, STRBP, ACACA, PIK3CB, PIK3R2, THRB.

G.8. Ephrin Receptor Signaling

Control Protein (0.62472) —

GRIN2A, CDC42, EGF, CRK, GNG7, PGF, VEGFA, PTK2, SHC1, PAK1, SDC2, PIK3CG, EFNB1, EPHA7, GRIN2B, SRC, PAK2, CFL1, CRKL, EPHA3, STAT3, WIPF1, SDCBP, PTPN11, PAK3, EPHA5, EPHB3.

3xTgAD Protein (0.21037) —

FYN, PXN, CFL1, CDC42, KALRN, GNB2L1, GNAI1, RAC1, JAK2, STAT3, GNAZ, ROCK1, VEGFA, GNAI2, ROCK2, ABI1, PTPN11, PAK3, RHOA, GNAO1.

G.9. G-Protein Coupled Receptor Signaling

Control Protein (0.3808) —

PDE7A, PDE4A, PDE1A, PDE4D, SHC1, SYNGAP1, PDE7B, PIK3CG, PLCB1, PRKCA, SRC, GRK4, EDNRB, PDE10A, PRKAR2A, PDE4B, STAT3, GRM4, PDE1C, CHRM5, GRM5, OPRD1, PRKAR2B, PRKACA, PRKCB, PRKAR1A.

3xTgAD Protein (0.13938) —

FYN, PTK2B, HTR4, ADRBK1, PDE10A, RGS7, PRKAR2A, GNAI1, RGS4, STAT3, PDE4B, GNAI2, HTR2C, PIK3C3, GNAO1, PRKACA, PIK3CB, PIK3R2, ADCY8, PRKAR1A.

G.10. Chemokine Signaling

Control Protein (0.23961) —

PTK2, NOX1, SRC, FOS, CCL4, CFL1, PIK3CG, CALM2, PLCB1, PRKCA, PRKCB.

3xTgAD Protein (0.03232) —

ROCK2, GNAI2, CFL1, PTK2B, RHOA, GNAI1.

G.11. Ceramide Signaling

Control Protein (0.15748) —

CTSD, PPP2CB, FOS, PPP2R1A, PPP2R2A, PIK3CG, PPP2R2B, PPP2R5E, PPP2R1B, PRKCZ.

3xTgAD protein (0) —

G.12. FGF (Fibroblast Growth Factor) Signaling

Control Protein (0.17423) —

FGFR3, PTPN11, FGF18, CRKL, PIK3CG, FGFR1, FGF23, FGFR2, CRK, STAT3, PRKCA.

3xTgAD Protein (0.0667352) —

PTPN11, PIK3C3, HGF, RAC1, PIK3CB, STAT3, PIK3R2, MAPKAPK2.

G.13. Toll-like Receptor Signaling

Control Protein (0.1644) —

TLR4, FOS, TLR5, TLR6, TLR3, ELK1, TLR9.

3xTgAD Protein (0.065562) —

PPARA, TLR5, MAP3K7IP2, LBP, ELK1.

G.14. Nitric Oxide Signaling

Control Protein (0.41157) —

GUCY1B2, GUCY1A3, GUCY2D, CALM2, PRKAR2A, PGF, VEGFA, PRKAR2B, PIK3CG, GUCY1A2, CAV1, PRKACA, PRKAR1A.

3xTgAD Protein (0.36801) —

VEGFA, HSP90AB1, GUCY2D, PRKCD, PIK3C3, GUCY2F, PRKAR2A, PRKACA, PIK3CB, PIK3R2, NOS3, PRKAR1A.

G.15. cAMP-Mediated Signaling

Control Protein (0.39295) —

GRK4, SRC, CNGA4, PDE7A, PDE10A, PRKAR2A, CALM2, PDE4A, PPP3CC, STAT3, PDE4B, GRM4, PDE1A, PDE4D, CNGA1, PDE1C, CHRM5, OPRD1, PRKAR2B, PDE7B, PRKACA, PKIA, PRKAR1A.

3xTgAD Protein (0.40848) —

AKAP12, HTR4, ADRBK1, PDE10A, RGS7, PRKAR2A, GNAI1, RGS4, AKAP3, PPP3CC, STAT3, PDE4B, CNGA1, GNAI2, AKAP4, GNAO1, PRKACA, CNGB1, PKIA, ADCY8, AKAP9, PRKAR1A.

G.16. TGF-β Signaling

Control protein (0) —

3xTgAD Protein (0.0236421) —

TGFB1, ACVR1, SMAD4, HNF4A, UBC, INHBC.

G.17. Neurotrophin/TRK Signaling

Control Protein (0.016851) —

SHC1, FOS, CDC42, PTPN11, PIK3CG.

3xTgAD Protein (0.0440592) —

NTRK2, CDC42, PTPN11, PIK3C3, PIK3CB, PIK3R2.

G.18. IGF-1 Signaling

Control Protein (0.49715) —

PRKAR2A, PTK2, SHC1, FOS, PRKAR2B, PTPN11, PIK3CG, PRKACA, CSNK2A1, CSNK2B, ELK1, PRKAR1A.

3xTgAD Protein (0.52722) —

PXN, YWHAH, PRKAR2A, NEDD4, YWHAQ, PTPN11, IRS1, PIK3C3, PRKACA, IGF1R, IRS2, PIK3CB, PIK3R2, ELK1, PRKAR1A.

G.19. Serotonin Receptor Signaling

Control protein (0) —

3xTgAD Protein (0.059769) —

HTR2C, HTR4, HTR3A, MAOA.

G.20. Glucocorticoid Receptor Signaling

Control protein (0) —

3xTgAD Protein (0.066) —

STAT5A, JAK1, YWHAH, HSPA14, RAC1, IL6, PPP3CC, STAT3, JAK2, NFKB1, MNAT1, IL1R2, HSP90AB1, TGFB1, PIK3C3, CEBPA, PRKACA, SMAD4, IL1B, PIK3CB, PIK3R2, ELK1.

G.21. Aryl Hydrocarbon Receptor Signaling

Control Protein (0.1218) —

SRC, CDK6, ALDH1L1, GSTO1, TGM2, CTSD, FOS, GSTM2, TGFB1, FASN, CDKN1B, ESR2, CDK2, FASLG, ATM, GSTK1.

3xTgAD Protein (0.31125) —

CYP1A1, NFIX, GSTM3, IL6, BAX, NFKB1, ARNT, MYC, AHRR, GSTM2, CCND2, HSP90AB1, TGFB1, ALDH1A3, IL1B, CDKN1B, AHR, MCM7, ATM.

G.22. Insulin Receptor Signaling

Control Protein (0.28288) —

TSC1, TRIP10, CRKL, PRKAR2A, CRK, VAMP2, PPP1R14B, PRKCZ, SHC1, PRKCI, PPP1R10, PTPN11, PIK3CG, TSC2, PRKACA.

3xTgAD Protein (0.5056) —

TSC1, FYN, JAK1, PRKAR2A, JAK2, VAMP2, INPP5D, MTOR, PTPN11, IRS1, PIK3C3, PRKACA, EIF2B1, PIK3CB, IRS2, PIK3R2, PRKAR1A.

G.23. Notch Signaling

Control Protein (0.0437248) —

DLL1, CNTN1, NCSTN, DLL3.

3xTgAD Protein (0.30609) —

NOTCH4, DLL1, NOTCH2, NCSTN, JAG1, NOTCH1, HEY1.

G.24. GABA Receptor Signaling

Control Protein (0.099214) —

GABRG2, UBQLN1, GABBR1, GABARAP, UBC, GABRA3.

3xTgAD Protein (0.4216) —

DNM1, NSF, SLC32A1, UBQLN1, GABBR1, MYO5B, GABRE, UBC, GABRA3.

G.25. VEGF Signaling

Control Protein (0.0252652) —

VEGFA, PTK2, SHC1, PIK3CG, PGF, PRKCA, PRKCB.

3xTgAD Protein (0.53464) —

EIF2S2, PXN, PTK2B, ACTB, NOS3, ARNT, ROCK2, VEGFA, ROCK1, PIK3C3, EIF2B1, PIK3CB, PIK3R2, ACTN4, ACTA1.

G.26. Integrin Signaling

Control protein (0) —

3xTgAD Protein (0.54604) —

RAP2B, FYN, RALA, CDC42, TSPAN3, ARF6, RHOB, PIK3C3, ARF4, PIK3R2, ACTA1, CAPN5, CAPN6, PXN, ACTB, RALB, RAC1, ITGA6, RHOJ.

H.

Heatmap Protein Position Key —

The individual position numbers are correlated to the specific multidimensional proteins represented by colored blocks in Figure 6. The following are the symbols of the proteins (the numbers between brackets refer to the position).

  1. adcyap1: adenylate cyclase activating polypeptide 1 (pituitary)
  2. adcyap1r1: adenylate cyclase activating polypeptide 1 (pituitary) receptor type I
  3. hap1: huntingtin-associated protein 1
  4. htr4: 5-hydroxytryptamine (serotonin) receptor 4
  5. ntrk2: neurotrophic tyrosine kinase, receptor, type 2
  6. Kalrn: kalirin, RhoGEF kinase
  7. klc1: kinesin light chain 1
  8. adrbk1: adrenergic, beta, receptor kinase 1
  9. agrn: agrin
  10. apod: apolipoprotein D
  11. app: amyloid beta (A4) precursor protein
  12. arhgef11: Rho guanine nucleotide exchange factor (GEF) 11
  13. arpp19: cAMP-regulated phosphoprotein, 19 kDa
  14. bace1: beta-site APP-cleaving enzyme 1
  15. ccs: copper chaperone for superoxide dismutase
  16. chgb: chromogranin B (secretogranin 1)
  17. flot1: flotillin 1
  18. flot2: flotillin 2
  19. gnb2l1: guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1
  20. hyou1: hypoxia up-regulated 1
  21. lphn1: latrophilin 1
  22. lphn2: latrophilin 2
  23. magi3: membrane associated guanylate kinase, WW and PDZ domain containing 3
  24. nefh: neurofilament, heavy polypeptide
  25. prdx6: peroxiredoxin 6
  26. pscd2: cytohesin 2
  27. rtn3: reticulon 3
  28. rtn4r: reticulon 4 receptor
  29. slc44a4: solute carrier family 44, member 4
  30. stxbp1: syntaxin binding protein 1
  31. abca1: ATP-binding cassette, sub-family A (ABC1), member 1
  32. abi1: abl-interactor 1
  33. adcy1: adenylate cyclase 1 (brain)
  34. adcy5: adenylate cyclase 5
  35. akap9: A kinase (PRKA) anchor protein 9
  36. aldh1a3: aldehyde dehydrogenase 1 family, member A3
  37. alox5: arachidonate 5-lipoxygenase
  38. arf6: ADP-ribosylation factor 6
  39. arhgef12: Rho guanine nucleotide exchange factor (GEF) 12
  40. atcay: ataxia, cerebellar, Cayman type
  41. atp2b1: ATPase, Ca++ transporting, plasma membrane 1
  42. atxn3: ataxin 3
  43. begain: brain-enriched guanylate kinase-associated homolog (rat)
  44. cabc1: chaperone, ABC1 activity of bc1 complex homolog (S. pombe)
  45. capn1: calpain 1, (mu/l) large subunit
  46. caskin1: CASK interacting protein 1
  47. casp7: caspase 7, apoptosis-related cysteine peptidase
  48. cd36: CD36 molecule (thrombospondin receptor)
  49. cfd: complement factor D (adipsin)
  50. clu: clusterin
  51. cpa2: carboxypeptidase A2 (pancreatic)
  52. cript: cysteine-rich PDZ-binding protein
  53. dpp6: dipeptidyl-peptidase 6
  54. espn: espin
  55. fdps: farnesyl diphosphate synthase
  56. filip1: filamin A interacting protein 1
  57. gna11: guanine nucleotide binding protein (G protein), alpha 11 (Gq class)
  58. gnai2: guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2
  59. gnao1: guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O
  60. gnaq: guanine nucleotide binding protein (G protein), q polypeptide
  61. gnaz: guanine nucleotide binding protein (G protein), alpha z polypeptide
  62. gpr56: G protein-coupled receptor 56
  63. hip1r: huntingtin interacting protein 1 related
  64. hmgcr: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase
  65. hsf1: heat shock transcription factor 1
  66. htr2c: 5-hydroxytryptamine (serotonin) receptor 2C
  67. itm2c: integral membrane protein 2C
  68. itpr3: inositol 1,4,5-triphosphate receptor, type 3
  69. lsamp: limbic system-associated membrane protein
  70. maoa: monoamine oxidase A
  71. map1lc3a: microtubule-associated protein 1 light chain 3 alpha
  72. mapkapk2: mitogen-activated protein kinase-activated protein kinase 2
  73. mark1: MAP/microtubule affinity-regulating kinase  1
  74. mdga2: MAM domain containing glycosylphosphatidylinositol anchor 2
  75. mpdz: multiple PDZ domain protein
  76. mpo: myeloperoxidase
  77. mpp7: membrane protein, palmitoylated 7 (MAGUK p55 subfamily member 7)
  78. ncam1: neural cell adhesion molecule 1
  79. ncam2: neural cell adhesion molecule 2
  80. ncdn: neurochondrin
  81. ndufs1: NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75 kDa (NADH-coenzyme Q reductase)
  82. ndufs7: NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20 kDa (NADH-coenzyme Q reductase)
  83. nes: nestin
  84. nlgn2: neuroligin 2
  85. nlgn3: neuroligin 3
  86. npc2: Niemann-Pick disease, type C2
  87. npdc1: neural proliferation, differentiation and control, 1
  88. npy5r: neuropeptide Y receptor Y5
  89. nsf: N-ethylmaleimide-sensitive factor
  90. padi2: peptidyl arginine deiminase, type II
  91. plcb4: phospholipase C, beta 4
  92. pxn: paxillin
  93. rab5a: RAB5A, member RAS oncogene family
  94. rgs4: regulator of G-protein signaling 4
  95. rgs7: regulator of G-protein signaling 7
  96. rims1: regulating synaptic membrane exocytosis 1
  97. rora: RAR-related orphan receptor A
  98. sh3gl1: SH3-domain GRB2-like 1
  99. sod2: superoxide dismutase 2, mitochondrial
  100. sst: somatostatin
  101. vldlr: very low density lipoprotein receptor
  102. camkk1: calcium/calmodulin-dependent protein kinase kinase 1, alpha
  103. cacna2d2: calcium channel, voltage-dependent, alpha 2/delta subunit 2
  104. vcp: valosin-containing protein
  105. stx1a: syntaxin 1A (brain)
  106. vgf: VGF nerve growth factor inducible
  107. calb2: calbindin 2
  108. prdx1: peroxiredoxin 1
  109. stmn2: stathmin-like 2
  110. vsnl1: visinin-like 1
  111. cdh2: cadherin 2, type 1, N-cadherin (neuronal)
  112. dbn1: drebrin 1
  113. oxr1: oxidation resistance 1
  114. gpsm1: G-protein signaling modulator 1 (AGS3-like, C. elegans)
  115. gmfb: glia maturation factor, beta
  116. cd2ap: CD2-associated protein
  117. centa1: ArfGAP with dual PH domains 1
  118. ncstn: nicastrin
  119. pak3: p21 protein (Cdc42/Rac)-activated kinase 3
  120. sncb: synuclein, beta
  121. calb1: calbindin 1
  122. cnr1: cannabinoid receptor 1 (brain)
  123. disc1: disrupted in schizophrenia 1
  124. dlgap2: discs, large (Drosophila) homolog-associated protein 2
  125. dlgap4: discs, large (Drosophila) homolog-associated protein 4
  126. dtnb: dystrobrevin, beta
  127. dvl1: dishevelled, dsh homolog 1 (Drosophila)
  128. exoc7: exocyst complex component 7
  129. gabbr1: gamma-aminobutyric acid (GABA) B receptor, 1
  130. panx1: pannexin 1
  131. pclo: piccolo (presynaptic cytomatrix protein)
  132. phactr3: phosphatase and actin regulator 3
  133. picalm: phosphatidylinositol binding clathrin assembly protein
  134. shank1: SH3 and multiple ankyrin repeat domains 1
  135. snap91: synaptosomal-associated protein, 91 kDa homolog (mouse)
  136. stmn4: stathmin-like 4
  137. sod1: superoxide dismutase 1, soluble
  138. synj2: synaptojanin 2
  139. tub: tubby homolog (mouse)
  140. snca: synuclein, alpha (non A4 component of amyloid precursor)
  141. park7: Parkinson disease (autosomal recessive, early onset) 7
  142. pcsk1n: proprotein convertase subtilisin/kexin type 1 inhibitor
  143. palm: Paralemmin
  144. vapb: VAMP (vesicle-associated membrane protein)-associated protein B and C
  145. cttn: cortactin
  146. cacna1a: calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
  147. celsr3: cadherin, EGF LAG seven-pass G-type receptor 3 (flamingo homolog, Drosophila)
  148. chl1: cell adhesion molecule with homology to L1CAM (close homolog of L1)
  149. chrm5: cholinergic receptor, muscarinic 5
  150. cnksr2: connector enhancer of kinase suppressor of Ras 2
  151. cnp: 2',3'-cyclic nucleotide 3' phosphodiesterase
  152. cntfr: ciliary neurotrophic factor receptor
  153. cntn1: contactin 1
  154. cplx1: complexin 1
  155. dag1: dystroglycan 1 (dystrophin-associated glycoprotein 1)
  156. dbndd2: dysbindin (dystrobrevin binding protein 1) domain containing 2
  157. dbnl: drebrin-like
  158. dclk2: doublecortin-like kinase 2
  159. dlgap1: discs, large (Drosophila) homolog-associated protein 1
  160. dscam: Down syndrome cell adhesion molecule
  161. ecel1: endothelin converting enzyme-like 1
  162. efnb1: ephrin-B1
  163. eml5: echinoderm microtubule associated protein like 5
  164. epha3: EPH receptor A3
  165. epha5: EPH receptor A5
  166. epha7: EPH receptor A7
  167. ephb3: EPH receptor B3
  168. erbb4: v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)
  169. evl: Enah/Vasp-like
  170. exoc5: exocyst complex component 5
  171. fzd9: frizzled homolog 9 (Drosophila)
  172. GABARAP: GABA(A) receptor-associated protein
  173. gabarapl2: GABA(A) receptor-associated protein-like  2
  174. gabrr3: gamma-aminobutyric acid (GABA) A receptor, alpha 3
  175. gcgr: glucagon receptor
  176. gng7: guanine nucleotide binding protein (G protein), gamma 7
  177. got1: glutamic-oxaloacetic transaminase 1, soluble (aspartate aminotransferase 1)
  178. got2: glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)
  179. gprc6a: G protein-coupled receptor, family C, group 6, member A
  180. gria1: glutamate receptor, ionotropic, AMPA 1
  181. grid2: glutamate receptor, ionotropic, delta 2
  182. grik4: glutamate receptor, ionotropic, kainate 4
  183. grin2a: glutamate receptor, ionotropic, N-methyl D-aspartate 2A
  184. grip1: glutamate receptor interacting protein 1
  185. gripap1: GRIP1 associated protein 1
  186. grk6: G protein-coupled receptor kinase 6
  187. opa1: optic atrophy 1 (autosomal dominant)
  188. pak1: p21 protein (Cdc42/Rac)-activated kinase 1
  189. pak2: p21 protein (Cdc42/Rac)-activated kinase 2
  190. pawr: PRKC, apoptosis, WT1, regulator
  191. phactr1: phosphatase and actin regulator 1
  192. pip5k1c: phosphatidylinositol-4-phosphate 5-kinase, type I, gamma
  193. plcb1: phospholipase C, beta 1 (phosphoinositide-specific)
  194. pld3: phospholipase D family, member 3
  195. ppfia3: protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 3
  196. ppid: peptidylprolyl isomerase D
  197. ppp2cb: protein phosphatase 2 (formerly 2A), catalytic subunit, beta isoform
  198. ppp2r2a: protein phosphatase 2 (formerly 2A), regulatory subunit B, alpha isoform
  199. prkar2b: protein kinase, cAMP-dependent, regulatory, type II, beta
  200. prnp: prion protein
  201. ptk2: PTK2 protein tyrosine kinase 2
  202. ptn: pleiotrophin
  203. ryr3: ryanodine receptor 3
  204. sdcbp: syndecan binding protein (syntenin)
  205. sh3gl3: SH3-domain GRB2-like 3
  206. shank2: SH3 and multiple ankyrin repeat domains 2
  207. sirt2: sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)
  208. smu1: smu-1 suppressor of mec-8 and unc-52 homolog (C. elegans)
  209. soat1: sterol O-acyltransferase 1
  210. sstr2: somatostatin receptor 2
  211. ssx2ip: synovial sarcoma, X breakpoint 2 interacting protein
  212. stau1: staufen, RNA binding protein, homolog 1 (Drosophila)
  213. stmn3: stathmin-like 3
  214. strn: striatin, calmodulin binding protein
  215. syn1: synapsin I
  216. syngap1: synaptic Ras GTPase activating protein 1 homolog (rat)
  217. synj2bp: synaptojanin 2 binding protein
  218. synpo: synaptopodin
  219. syt11: synaptotagmin XI
  220. trap1: TNF receptor-associated protein 1
  221. trpc2: transient receptor potential cation channel, subfamily C, member 2 (pseudogene)
  222. trpc4: transient receptor potential cation channel, subfamily C, member 4
  223. trpc5: transient receptor potential cation channel, subfamily C, member 5
  224. wnt7a: wingless-type MMTV integration site family, member 7A
  225. tuba1a: tubulin, alpha 1a
  226. vipr2: vasoactive intestinal peptide receptor 2
  227. trak2: trafficking protein, kinesin binding 2
  228. snx17: sorting nexin 17
  229. psd: pleckstrin and Sec7 domain containing
  230. ppp2r2b: protein phosphatase 2 (formerly 2A), regulatory subunit B, beta isoform
  231. ppp1r9b: protein phosphatase 1, regulatory (inhibitor) subunit 9B
  232. grm5: glutamate receptor, metabotropic 5
  233. grk5: G protein-coupled receptor kinase 5
  234. grin2b: glutamate receptor, ionotropic, N-methyl D-aspartate 2B
  235. grik1: glutamate receptor, ionotropic, kainate 1
  236. grasp: GRP1 (general receptor for phosphoinositides 1)-associated scaffold protein
  237. gipc1: GIPC PDZ domain containing family, member  1
  238. dpysl4: dihydropyrimidinase-like 4
  239. dpysl3: dihydropyrimidinase-like 3
  240. dgkb: diacylglycerol kinase, beta 90 kDa
  241. ddn: dendrin
  242. cit: citron (rho-interacting, serine/threonine kinase 21)
  243. grm4: glutamate receptor, metabotropic 4
  244. ctnnd2: catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein).

I.

Receptor-specific protein interaction networks in lipid raft extracts from control animals. IPA-generated receptor-specific protein lists from control lipid raft samples were clustered into coherent functional interaction networks. Focus molecules (BOLD in “molecules in network”) denote the proteins that are present in the predicted reaction network as well as the experimental input protein set. The following are different types of interaction networks.

(1) Control: cell signaling, nucleic acid metabolism, small molecule biochemistry; score: 32; focus molecule: 15; molecules in network: ADCY, Akt, Beta-Arrestin, CD4, CHRM5, CNTFR, Creb, EDNRB, ERK1/2, FSHR, GABBR1, GCGR, Gpcr, GPR3, GPR12, GPR20, GPR34, GPR65, GPR161, GRM5, hCG, Mapk, OPRD1, OVGP1, P2RY6, P2RY11, PDGF BB, PI3K, Pkc(s), PTGER2, SFRP4, SSTR2, THBD, UNC5B, VIPR2.

(2) Control: infectious disease, antigen presentation, antimicrobial response; score: 31; focus molecule: 15; molecules in network: Ap1, CHRNB3, CHRNB4, CHRNG, CLDN4, CNR1, CXADR, G alphai, Ifn, IFN Beta, IFN TYPE 1, IgG, IKK (complex), IL-1R/TLR, IL12 (complex), Il12 (family), Interferon alpha, IRAK, IRF, NFkB (complex), NRG, OSMR, P38 MAPK, SMO, TACR1, Tlr, TLR3, TLR4, TLR5, TLR6, TLR9, TSHR, Ubiquitin.

(3) Control: cellular development tumor morphology, cell death; score: 18; focus molecule: 10; molecules in network: APOL5, ARR3, ARTN, ASB16, Cadherin (E,N,P,VE), CELSR2, CELSR3, CTNNB1, CTNNβ-CDHE/N, DAG1, EVX1, FZD9, GDNF, GFRA1, GFRA3, GLTSCR1, GPRC6A, GRB2, GRM4, HRH4, KCNN1, OPN1LW, OPN1SW, PALM2-AKAP2, PHACTR2, PRICKLE3, PTH2R, SAG, SEPN1, SHROOM2, SRC.

(4) Control: carbohydrate metabolism; score: 2; focus molecule: 1; molecules in network: CLEC4A, IL13.

(5) Control: cell-to-cell signaling and interaction, nervous system development and function; score: 2; focus molecule: 1; molecules in network: PRPH2, ROM1.

(6) Control: protein synthesis, molecular transport, protein trafficking; score: 2; focus molecule: 1; molecules in network: GABRR3, PRKCZ, SQSTM1.

J.

Receptor-specific protein interaction networks in lipid raft extracts from 3xTgAD animals. IPA-generated receptor-specific protein lists from 3xTgAD lipid raft samples were clustered into coherent functional interaction networks. Focus molecules (BOLD in “molecules in network”) denote the proteins that are present in the predicted reaction network as well as the experimental input protein set. The following are different types of interaction networks.

(1) 3xTgAD: metabolic disease, endocrine system disorders, cell signaling; score: 45; focus molecule: 18; molecules in network: ADCYAP1R1, Ap1, CD36, CD86, CNR1, Creb, CREB-NFkB, CXADR, ERK, ERK1/2, GABBR1, GPR56, hCG, HTR4, HTR2C, IGF1R, IGF2R, IgG, IL12 (complex), IL1R2, Insulin, Jnk, LDL, LIFR, LRPAP1, Mapk, MIP1, NFkB (complex), NPR2, OVGP1, P38 MAPK, Pkc(s), TLR5, TNFRSF14, TSHR.

(2) 3xTgAD: cell signaling, nucleic acid metabolism, small molecule biochemistry; score: 13; focus molecule: 7; molecules in network: AATK, ABR, AKR1A1, BPI, CACNG5, CRYM, cyclic AMP, CYP26B1, DHRS3, DLG4, GH1, Histone h3, HSD17B11, KCTD11, KIF3C, LAP3, LPHN1, LPHN2, OPN1LW, OPN1SW, P2RY11, PTCH1, PTH2R, RLN3, RN5S, ROBO1, ROS1, RXFP1, RXFP2, SERPINB8, TMEM49, TNF, USP3.

(3) 3xTgAD: cell signaling, cellular function and maintenance, molecular transport; score: 2; focus molecule: 1; molecules in network: CFTR, FREQ, IL1RAPL1, MYD88.

(4) 3xTgAD: cell-to-cell signaling and interaction, cellular function and maintenance, cellular movement; score: 2; focus molecule: 1; molecules in network: GPR1, PAX3, PRDM5.

(5) 3xTgAD: behavior, digestive system development and function, cell morphology; score: 2; focus molecule: 1; molecules in network: NPY, NPY5R, PPY, PYY, SSB.

(6) 3xTgAD: cancer, reproductive system disease, gene expression; score: 2; focus molecule: 1; molecules in network: FOS, MIR103-1, MIR103-2, MIR107, MIRLET7G, MYC, OMG, RHOA, RTN4R.

References

1. Ashford JW. APOE genotype effects on Alzheimer’s disease onset and epidemiology. Journal of Molecular Neuroscience. 2004;23(3):157–165. [PubMed]
2. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends in Neurosciences. 2004;27(10):589–594. [PubMed]
3. Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M. Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nature Neuroscience. 1998;1(5):355–358. [PubMed]
4. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–356. [PubMed]
5. Maudsley S, Mattson MP. Protein twists and turns in Alzheimer disease. Nature Medicine. 2006;12(4):392–393. [PubMed]
6. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240(4852):622–630. [PubMed]
7. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(5):1977–1981. [PubMed]
8. Schengrund C-L. Lipid rafts: keys to neurodegeneration. Brain Research Bulletin. 2010;82(1-2):7–17. [PubMed]
9. Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010;327(5961):46–50. [PubMed]
10. Gellermann GP, Appel TR, Tannert A, et al. Raft lipids as common components of human extracellular amyloid fibrils. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(18):6297–6302. [PubMed]
11. Kubo S-I, Nemani VM, Chalkley RJ, et al. A combinatorial code for the interaction of α-synuclein with membranes. Journal of Biological Chemistry. 2005;280(36):31664–31672. [PubMed]
12. Morris RJ, Parkyn CJ, Jen A. Traffic of prion protein between different compartments on the neuronal surface, and the propagation of prion disease. FEBS Letters. 2006;580(23):5565–5571. [PubMed]
13. Riddell DR, Christie G, Hussain I, Dingwall C. Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Current Biology. 2001;11(16):1288–1293. [PubMed]
14. Grimm MOW, Grimm HS, Tomic I, Beyreuther K, Hartmann T, Bergmann C. Independent inhibition of Alzheimer disease β- and γ-secretase cleavage by lowered cholesterol levels. Journal of Biological Chemistry. 2008;283(17):11302–11311. [PubMed]
15. Kalvodova L, Kahya N, Schwille P, et al. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. Journal of Biological Chemistry. 2005;280(44):36815–36823. [PubMed]
16. Yamamoto N, Hirabayashi Y, Amari M, et al. Assembly of hereditary amyloid β-protein variants in the presence of favorable gangliosides. FEBS Letters. 2005;579(10):2185–2190. [PubMed]
17. Yamamoto N, Matsuzaki K, Yanagisawa K. Cross-seeding of wild-type and hereditary variant-type amyloid β-proteins in the presence of gangliosides. Journal of Neurochemistry. 2005;95(4):1167–1176. [PubMed]
18. Ariga T, McDonald MP, Yu RK. Role of ganglioside metabolism in the pathogenesis of Alzheimer’s disease—a review. Journal of Lipid Research. 2008;49(6):1157–1175. [PMC free article] [PubMed]
19. Williamson R, Usardi A, Hanger DP, Anderton BH. Membrane-bound β-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. FASEB Journal. 2008;22(5):1552–1559. [PubMed]
20. Bhaskar K, Yen S-H, Lee G. Disease-related modifications in tau affect the interaction between Fyn and tau. Journal of Biological Chemistry. 2005;280(42):35119–35125. [PubMed]
21. Fulga TA, Elson-Schwab I, Khurana V, et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nature Cell Biology. 2007;9(2):139–148. [PubMed]
22. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s Disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron. 2003;39(3):409–421. [PubMed]
23. Nelson RL, Guo Z, Halagappa VM, et al. Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Experimental Neurology. 2007;205(1):166–176. [PMC free article] [PubMed]
24. Martin B, Brenneman R, Becker KG, Gucek M, Cole RN, Maudsley S. iTRAQ analysis of complex proteome alterations in 3xTgAD Alzheimer’s mice: understanding the interface between physiology and disease. PLoS ONE. 2008;3(7, article e2750) [PMC free article] [PubMed]
25. Stranahan AM, Lee K, Becker KG, et al. Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice. Neurobiology of Aging. 2010;31(11):1937–1949. [PMC free article] [PubMed]
26. Maudsley S, Pierce KL, Zamah AM, et al. The β2-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. Journal of Biological Chemistry. 2000;275(13):9572–9580. [PubMed]
27. Calvano SE, Xiao W, Richards DR, et al. A network-based analysis of systemic inflammation in humans. Nature. 2005;437(7061):1032–1037. [PubMed]
28. Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Research Reviews. 2006;5(3):332–353. [PMC free article] [PubMed]
29. Murray J, Capaldi RA. Screening for the metabolic basis of neurodegeneration: developing a focused proteomic approach. Annals of the New York Academy of Sciences. 2008;1147:348–357. [PubMed]
30. Brewer GJ. Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories. Experimental Gerontology. 2010;45(3):173–179. [PMC free article] [PubMed]
31. Allen JA, Halverson-Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signalling. Nature Reviews Neuroscience. 2007;8(2):128–140. [PubMed]
32. Petersen SL, Krishnan S, Hudgens ED. The aryl hydrocarbon receptor pathway and sexual differentiation of neuroendocrine functions. Endocrinology. 2006;147(6):S33–S42. [PubMed]
33. Caltagarone J, Jing Z, Bowser R. Focal adhesions regulate Aβ signaling and cell death in Alzheimer’s disease. Biochimica et Biophysica Acta. 2007;1772(4):438–445. [PMC free article] [PubMed]
34. Maudsley S, Martin B, Luttrell LM. G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics. Current Alzheimer Research. 2007;4(1):3–19. [PubMed]
35. Maudsley S, Martin B, Luttrell LM. The origins of diversity and specificity in G protein-coupled receptor signaling. Journal of Pharmacology and Experimental Therapeutics. 2005;314(2):485–494. [PMC free article] [PubMed]
36. Inestrosa NC, Arenas E. Emerging roles of Wnts in the adult nervous system. Nature Reviews Neuroscience. 2010;11(2):77–86. [PubMed]
37. Johnson JA, Johnson DA, Kraft AD, et al. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Annals of the New York Academy of Sciences. 2008;1147:61–69. [PMC free article] [PubMed]
38. Marlatt MW, Lucassen PJ. Neurogenesis and Alzheimer's disease: biology and pathophysiology in mice and men. Current Alzheimer Research. 2010;7(2):113–125. [PubMed]
39. Cohen E, Paulsson JF, Blinder P, et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009;139(6):1157–1169. [PMC free article] [PubMed]
40. Freude S, Schilbach K, Schubert M. The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer’s disease: from model organisms to human disease. Current Alzheimer Research. 2009;6(3):213–223. [PubMed]
41. Araki W, Kume H, Oda A, Tamaoka A, Kametani F. IGF-1 promotes β-amyloid production by a secretase-independent mechanism. Biochemical and Biophysical Research Communications. 2009;380(1):111–114. [PubMed]
42. Martin B, Brenneman R, Golden E, et al. Growth factor signals in neural cells: coherent patterns of interaction control multiple levels of molecular and phenotypic responses. Journal of Biological Chemistry. 2009;284(4):2493–2511. [PMC free article] [PubMed]
43. Ushkaryov YA, Rohou A, Sugita S. alpha-Latrotoxin and its receptors. Handbook of Experimental Pharmacology. 2008;184:171–206. [PMC free article] [PubMed]
44. Reilly JO, Karavanova ID, Williams KP, Mahanthappa NK, Allendoerfer KL. Cooperative effects of Sonic hedgehog and NGF on basal forebrain cholinergic neurons. Molecular and Cellular Neuroscience. 2002;19(1):88–96. [PubMed]
45. Thathiah A, De Strooper B. G protein-coupled receptors, cholinergic dysfunction, and Aβ toxicity in Alzheimer's disease. Science Signaling. 2009;2(93):p. re8. [PubMed]

Articles from International Journal of Alzheimer's Disease are provided here courtesy of Hindawi