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1.  Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer’s disease 
Aging cell  2012;11(4):559-568.
Summary
The cause of elevated level of amyloid β-peptide (Aβ42) in common late-onset sporadic (AD) has not been established. Here we show that the membrane lipid peroxidation product 4-hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD, and that it enhances γ-secretase activity and Aβ42 production in neurons. The γ-secretase substrate receptor, nicastrin was found to be modified by HNE in cultured neurons and in brain specimens from AD patients, in which HNE-nicastrin levels were found to be correlated with increased γ-secretase activity and Aβ plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ-secretase activity and Aβ42 production by HNE were blocked by an HNE-scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aβ42 production in AD, and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP.
doi:10.1111/j.1474-9726.2012.00817.x
PMCID: PMC4217088  PMID: 22404891
Alzheimer’s disease; oxidative stress; amyloid; lipid peroxidation; γ-secretase; nicastrin
2.  Molecular changes in brain aging and Alzheimer’s disease are mirrored in experimentally silenced cortical neuron networks 
Neurobiology of aging  2010;33(1):205.e1-205.e18.
Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer’s disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca2+ signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca2+-mediated degeneration.
doi:10.1016/j.neurobiolaging.2010.08.012
PMCID: PMC3027841  PMID: 20947216
Alzheimer’s disease; Aging; GABA; Activity; Homeostatic disinhibition; Interneuron; Calcium; Synaptic scaling
3.  Proteomics Analysis of Brain Proteins in APP/PS-1 Human Double Mutant Knock-in Mice with Increasing Amyloid β-Peptide Deposition: Insights into the Effects of in vivo Treatment with N-Acetylcysteine as a Potential Therapeutic Intervention in Mild Cognitive Impairment and Alzheimer Disease 
Proteomics  2011;11(21):4243-4256.
Proteomics analyses were performed on the brains of wild-type (WT) controls and an Alzheimer’s disease (AD) mouse model, APP/PS-1 human double mutant knock in mice. Mice were given either drinking water or water supplemented with N-acetylcysteine (NAC) (2mg/kg body weight) for a period of five months. The time periods of treatment correspond to ages prior to Aβ deposition (i.e., 4–9 months), resembling human mild cognitive impairment (MCI), and after Aβ deposition (i.e., 7–12 months), more closely resembling advancing stages of AD. Substantial differences exist between the proteomes of WT and APP/PS-1 mice at 9 or 12 months, indicating that Aβ deposition and oxidative stress lead to downstream changes in protein expression. Altered proteins are involved in energy-related pathways, excitotoxicity, cell cycle signaling, synaptic abnormalities, and cellular defense and structure. Overall, the proteomic results support the notion that NAC may be beneficial for increasing cellular stress responses in WT mice and for influencing the levels of energy- and mitochondrial related proteins in APP/PS-1 mice.
doi:10.1002/pmic.201000523
PMCID: PMC3517055  PMID: 21954051
APP/PS1; N-acetylcysteine; protein oxidation; proteomics; oxidative stress; Alzheimer disease; Mild cognitive impairment
4.  Alzheimer Disease Pathology in Cognitively Healthy Elderly:A Genome-wide Study 
Neurobiology of aging  2010;32(12):2113-2122.
Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 344 non-demented subjects with autopsy (201 subjects with low and 143 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided genome-wide significant evidence that variants in the RELNgene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
doi:10.1016/j.neurobiolaging.2010.01.010
PMCID: PMC2990809  PMID: 20452100
5.  Proteomics Identification of Specifically Carbonylated Brain Proteins in APPNLh/APPNLh x PS-1P264L/PS-1P264L Human Double Mutant Knock-in Mice Model of Alzheimer Disease as a Function of Age 
Journal of proteomics  2011;74(11):2430-2440.
Alzheimer disease (AD) is the most common type of dementia and is characterized pathologically by the presence of neurofibrillary tangles (NFTs), senile plaques (SPs), and loss of synapses. The main component of SP is amyloid-beta peptide (Aβ), a 39 to 43 amino acid peptide, generated by the proteolytic cleavage of amyloid precursor protein (APP) by the action of beta- and gamma-secretases. The presenilins (PS) are components of the γ-secretase, which contains the protease active center. Mutations in PS enhance the production of the Aβ42 peptide. To date, more than 160 mutations in PS1 have been identified. Many PS mutations increase the production of the β-secretase-mediated C-terminal (CT) 99 amino acid-long fragment (CT99), which is subsequently cleaved by γ-secretase to yield Aβ peptides. Aβ has been proposed to induce oxidative stress and neurotoxicity. Previous studies from our laboratory and others showed an age-dependent increase in oxidative stress markers, loss of lipid asymmetry, and Aβ production and amyloid deposition in the brain of APP/PS1 mice. In the present study, we used APPNLh/APPNLh x PS-1P246L/PS-1P246L human double mutant knock-in APP/PS-1 mice to identify specific targets of brain protein carbonylation in an age-dependent manner. We found a number of proteins that are oxidatively modified in APP/PS1 mice compared to age-matched controls. The relevance of the identified proteins to the progression and pathogenesis of AD is discussed.
doi:10.1016/j.jprot.2011.06.015
PMCID: PMC3199338  PMID: 21726674
Oxidative stress; Amyloid β-peptide; Alzheimer’s disease; Presenilin-1; Redox proteomics; Protein carbonyls
6.  Lewy Body Pathology in Normal Elderly Subjects 
Lewy body and Lewy neurite formation are the hallmark neuropathological findings in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB), and other alpha-synucleinopathies. They also have been described in the brains of normal older individuals and referred to as incidental Lewy body disease. The purpose of this study was to determine the prevalence of Lewy bodies and Lewy neurites (Lewy body pathology; LBP) in 139 autopsies from our normal volunteer control group of the University of Kentucky Alzheimer’s Disease Center. All subjects were followed longitudinally and were cognitively normal without any type of movement disorder, neuropsychiatric features, or other CNS findings. Thirty-three out of 139 normal subjects contained LBP in various brain regions. The most common regions involved were the medulla (26%), amygdala (24%), pons (20%), and midbrain (20%). No mean statistical differences were found between those with and without LBP on any demographic or cognitive variable, Braak stage, or neurofibrillary tangle and neuritic plaque quantitation. The high prevalence of LBP in our elderly, well educated group is not clear although it does not appear to be related to aging or the presence of AD pathology. Overall, our findings support the concept that incidental Lewy body disease most likely represents preclinical or presymptomatic PD, PDD or DLB.
doi:10.1097/NEN.0b013e3181ac10a7
PMCID: PMC2704264  PMID: 19535990
Aging; Alpha-synucleinopathies; Lewy bodies; Lewy neurites
7.  NEURON SPECIFIC TOXICITY OF OLIGOMERIC BETA AMYLOID: Implications for JUN-kinase and oxidative stress 
Recent studies have demonstrated a potential role for oligomeric forms of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD.
doi:10.3233/JAD-2010-101161
PMCID: PMC3412400  PMID: 20858948
Alzheimer’s disease; beta amyloid; neurotoxicity; protein oxidation
8.  Increased Protein Hydrophobicity in Response to Aging and Alzheimer’s disease 
Free radical biology & medicine  2010;48(10):1330-1337.
Increased levels of misfolded and damaged proteins occur in response to brain aging and Alzheimer’s disease (AD), which presumably increases the amount of aggregation prone proteins via elevations in hydrophobicity. The proteasome is an intracellular protease which degrades oxidized and ubiquitinated proteins, with the function of the proteasome known to be impaired in response to both aging and AD. In the present study we sought to determine the potential for increased levels of protein hydrophobicity occurring in response to aging and AD, identify the contribution of proteasome inhibition to increased protein hydrophobicity, and lastly to identify the contribution of ubiquitinated and oxidized proteins to the pool of hydrophobic proteins. In our studies we identified that aging and AD exhibited increases in protein hydrophobicity as detected using Bis-ANS, with dietary restriction (DR) significantly decreasing age-related increases in protein hydrophobicity. Affinity chromatography purification of hydrophobic proteins from aging and AD brains identified increased levels of oxidized and ubiquitinated proteins in the pool of hydrophobic proteins. Pharmacological inhibition of the proteasome in neurons, but not astrocytes, resulted in an increase in protein hydrophobicity. Taken together, these data indicate that there is a relationship between increased protein oxidation and protein ubiquitination and elevations in protein hydrophobicity within the aging and AD brain, which may be mediated in part by impaired proteasome activity in neurons. Our studies also suggest a potential role for decreased oxidized and hydrophobic proteins in mediating the beneficial effects of DR.
doi:10.1016/j.freeradbiomed.2010.02.012
PMCID: PMC3175611  PMID: 20188163
9.  Alterations of Zinc Transporter Proteins ZnT-1, ZnT-4 and ZnT-6 in Preclinical Alzheimer's Disease Brain 
Our previous studies demonstrate alterations of zinc (Zn) transporter proteins ZnT-1, ZnT-4, and ZnT-6 in vulnerable brain regions of subjects with mild cognitive impairment (MCI), early and late stage Alzheimer's disease (AD) and suggest that disruptions of Zn homeostasis may play a role in the pathogenesis of AD. ZnT-1 exports Zn from the cytosol to extracellular compartments, ZnT-4 transports Zn from the cytosol to lysosomes and endosomes, and ZnT-6 sequesters Zn in the trans-Golgi network. A preclinical stage of AD (PCAD) has been described in which subjects show no overt clinical manifestations of AD but demonstrate significant AD pathology at autopsy. To determine if alterations of ZnT proteins occur in PCAD we measured ZnT-1, ZnT-4, and ZnT-6 in the hippocampus/parahippocampal gyrus (HPG) and cerebellum (CER) of 7 PCAD subjects and 7 age matched normal control (NC) subjects using Western blot analysis and immunohistochemistry. Our results show a significant decrease (P < 0.05) of ZnT-1 in HPG of PCAD subjects, along with an increase of ZnT-4 in PCAD CER and ZnT-6 in PCAD HPG, but a significant decrease in PCAD CER compared to NC subjects. Confocal microscopy of representative sections of HPG shows altered ZnTs are associated with neurons immunopositive for MC-1, a monoclonal antibody that identifies neurons early in formation of neurofibrillary tangles. Overall, our results suggest that alterations in Zn transport proteins may contribute to the pathology observed in PCAD subjects before onset of clinical symptoms.
doi:10.1111/j.1750-3639.2009.00283.x
PMCID: PMC3175637  PMID: 19371353
zinc transporter-1; zinc transporter-4; zinc transporter-6; preclinical Alzheimer's disease
11.  Preclinical Alzheimer Disease: Brain Oxidative Stress, Aβ Peptide & Proteomics 
Neurobiology of disease  2010;39(2):221-228.
Alzheimer disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory loss and subsequent dementia and neuropathologically by senile plaques, neurofibrillary tangles, and synapse loss. Interestingly, a small percentage of individuals with normal antemortem psychometric scores meet the neuropathological criteria for AD (termed `preclinical' AD (PCAD)). In this study, inferior parietal lobule (IPL) from PCAD and control subjects were compared for oxidative stress markers by immunochemistry, amyloid beta-peptide by ELISA, and identification of protein expression differences by proteomics. We observed a significant increase in highly insoluble monomeric Aβ42, but no significant differences in oligomeric Aβ nor in oxidative stress measurements between controls and PCAD subjects. Expression proteomics identified proteins whose trends in PCAD are indicative of cellular protection, possibly correlating with previous studies showing no cell loss in PCAD. Our analyses may reveal processes involved in a period of protection from neurodegeneration that mimic the clinical phenotype of PCAD.
doi:10.1016/j.nbd.2010.04.011
PMCID: PMC2885559  PMID: 20399861
Preclinical Alzheimer; oxidative stress; amyloid beta; proteomics; brain; inferior parietal lobule; IPL
12.  NOX Activity Is Increased in Mild Cognitive Impairment 
Antioxidants & Redox Signaling  2010;12(12):1371-1382.
Abstract
This study was undertaken to investigate the profile of NADPH oxidase (NOX) in the clinical progression of Alzheimer's disease (AD). Specifically, NOX activity and expression of the regulatory subunit p47phox and the catalytic subunit gp91phox was evaluated in affected (superior and middle temporal gyri) and unaffected (cerebellum) brain regions from a longitudinally followed group of patients. This group included both control and late-stage AD subjects, and also subjects with preclinical AD and with amnestic mild cognitive impairment (MCI) to evaluate the profile of NOX in the earliest stages of dementia. Data show significant elevations in NOX activity and expression in the temporal gyri of MCI patients as compared with controls, but not in preclinical or late-stage AD samples, and not in the cerebellum. Immunohistochemical evaluations of NOX expression indicate that whereas microglia express high levels of gp91phox, moderate levels of gp91phox also are expressed in neurons. Finally, in vitro experiments showed that NOX inhibition blunted the ability of oligomeric amyloid beta peptides to injure cultured neurons. Collectively, these data show that NOX expression and activity are upregulated specifically in a vulnerable brain region of MCI patients, and suggest that increases in NOX-associated redox pathways in neurons might participate in the early pathogenesis of AD. Antioxid. Redox Signal. 12, 1371–1382.
doi:10.1089/ars.2009.2823
PMCID: PMC2864654  PMID: 19929442
13.  Age-related loss of phospholipid asymmetry in APPNLh/APPNLh × PS-1P264L/PS-1P264L human double knock-in mice: Relevance to Alzheimer disease 
Neurobiology of disease  2010;38(1):104-115.
Using APPNLh/APPNLh×PS-1P246L/PS-1P246L human double knock-in (APP/PS-1) mice, we examined whether phosphatidylserine (PtdSer) asymmetry is significantly altered in brain of this familial Alzheimer disease mouse model in an age-dependent manner as a result of oxidative stress, toxic Aβ(1–42) oligomer production, and/or apoptosis. Annexin V (AV) and NBD-PS fluorescence in synaptosomes of wild-type (WT) and APP/PS-1 mice were used to determine PtdSer exposure with age, while Mg2+ATPase activity was determined to correlate PtdSer asymmetry changes with PtdSer translocase, flippase, activity. AV and NBD-PS results demonstrated significant PtdSer exposure beginning at 9 months compared to 1 month-old WT controls for both assays, a trend that was exacerbated in synaptosomes of APP/PS-1 mice. Decreasing Mg2+ATPase activity confirms that the age-related loss of PtdSer asymmetry is likely due to loss of flippase activity, more prominent in APP/PS-1 brain. Two-site sandwich ELISA on SDS- and FA-soluble APP/PS-1 brain fractions were conducted to correlate Aβ(1–40) and Aβ(1–42) levels with age-related trends determined from the AV, NBD-PS, and Mg2+ATPase assays. ELISA revealed a significant increase in both SDS- and FA-soluble Aβ(1–40) and Aβ(1–42) with age, consistent with PtdSer and flippase assay trends. Lastly, because PtdSer exposure is affected by pro-apoptotic caspase-3, levels of both latent and active forms were measured. Western blotting results demonstrated an increase in both active fragments of caspase-3 with age, while levels of pro-caspase-3 decrease. These results are discussed with relevance to loss of lipid asymmetry and consequent neurotoxicity in brain of subjects with Alzheimer disease.
doi:10.1016/j.nbd.2010.01.004
PMCID: PMC2834848  PMID: 20083199
Amyloid precursor protein (APP); presenilin-1 (PS-1); familial Alzheimer disease (FAD); phosphatidylserine (PtdSer); phospholipid asymmetry; oxidative stress; lipid peroxidation; toxic Aβ(1–42) oligomers; apoptosis; caspase-3
14.  Comparison of Recruitment Efforts Targeted at Primary Care Physicians versus the Community At Large for Participation in Alzheimer's Disease Clinical Trials 
Inefficient and delayed recruitment into clinical trials in Alzheimer's disease are major obstacles impeding progress in the discovery of more effective therapeutic strategies to combat this disease. Despite widespread recognition of this problem, limited empirical data demonstrating the effectiveness of specific recruitment strategies are available to guide recruitment endeavors. The present study was designed to evaluate the effectiveness of recruitment efforts targeting either the primary care health professionals (PCP) or patients and families with a community grass-roots outreach event (COE). The primary outcome measure was actual study recruitment and participation in the four months post-intervention. No research subjects were recruited from the PCP intervention, while 69 subjects were recruited into clinical studies from the COE activity (0% vs. 28%, P<0.0001, Fisher exact test). Barriers to recruitment success in the PCP arm included a perception of perceived harm to subjects from research participation and fear of losing patients through clinical research participation. Our results suggest that outreach efforts directed at the potential study subject/caregiver are not only cost-effective but are able to easily accomplish the desired result of direct recruitment into clinical research studies.
doi:10.1097/WAD.0b013e3181aba927
PMCID: PMC2877762  PMID: 19571728
Alzheimer's disease; clinical trial; recruitment
15.  Association between male gender and cortical Lewy body pathology in large autopsy series 
Journal of neurology  2010;257(11):1875-1881.
Sex-linked factors may alter risk for neurodegenerative diseases. Definitive diagnoses are not established until autopsy, so neuropathological studies are critical. There have not been reported gender-related differences in neocortical Lewy bodies (LBs) using large multi-center autopsy series. We evaluated the associations between gender and pathologically characterized neurodegenerative diseases. Cases with Alzheimer's disease (AD), neocortical LBs, AD + neocortical LBs, or neither pathology were evaluated as separate groups. Results were corrected for possible confounders including age at death, smoking history, and education. The settings were the University of Kentucky Alzheimer's Disease Center and the National Alzheimer's Coordinating Center (NACC) Registry autopsy series; 3,830 subjects met inclusion criteria. Patients with neocortical (“diffuse”) or intermediate (“limbic”) LB pathologies tended to be male (male:female odds ratios ∼2.9 with 95% CI 2.02–4.18). The preponderance of males dying with neocortical LB pathology was seen consistently across age groups and was not due to the potential confounders evaluated. By contrast, individuals dying with AD pathology were more likely to be female if dying over 80 (male:female odds ratio 0.66, 95% CI 0.50–0.88), but that tendency was not seen in individuals dying with AD pathology prior to age 80. Increased understanding of the male predominance in neocortical LB pathology may help guide clinicians, because males are more likely to be “undercalled” for neocortical LBs clinically, and females are more likely to be “overcalled” (P < 0.05 for both). Males are far more likely than females to die with neocortical LB pathology. This phenomenon may help guide medical practice including clinical trial study design.
doi:10.1007/s00415-010-5630-4
PMCID: PMC3040648  PMID: 20563821
DLB; Synuclein; Human; Dementia; Neuropathology
16.  Clinicopathologic Correlations in a Large Alzheimer Disease Center Autopsy Cohort: Neuritic Plaques and Neurofibrillary Tangles “Do Count” When Staging Disease Severity 
There is uncertainty regarding the association of cognitive decline in Alzheimer disease (AD) with classic histopathologic features—neurofibrillary tangles (NFTs) and “neuritic” amyloid plaques (NPs). This uncertainty fuels doubts about the diagnostic importance of NFTs and NPs and leads to confusion regarding hypotheses of AD pathogenesis. Three hundred ninety subjects who underwent longitudinal premortem clinical workup and postmortem quantitative neuropathologic assessment served as the group to address this issue. Subjects with concomitant brain disease(s) were analyzed independently to more accurately assess the contribution of distinct pathologies to cognitive decline. More than 60% of patients of all age groups had important non-AD brain pathologies. However, subjects without superimposed brain diseases showed strong correlations between AD-type pathology counts (NFTs > NPs) and premortem Mini-Mental State Examination scores. The observed correlation was stronger in isocortex than in allocortex and was maintained across age groups including patients older than 90 years. A theoretical model is proposed in which our results are interpreted to support the “amyloid cascade hypothesis” of AD pathogenesis. Our data show that there are many important contributory causes to cognitive decline in older persons. However, NFTs and NPs should not be dismissed as irrelevant in AD based on clinicopathologic correlation.
doi:10.1097/nen.0b013e31815c5efb
PMCID: PMC3034246  PMID: 18090922
Alzheimer disease; Amyloid; Cerebrovascular; Neurofibrillary tangles (NFTs); Plaques
17.  Proteomic identification of nitrated brain proteins in early Alzheimer’s disease inferior parietal lobule 
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline in multiple cognitive domains. Its pathological hallmarks include senile plaques and neurofibrillary tangles. Mild cognitive impairment (MCI) is the earliest detectable stage of AD with limited symptomology and no dementia. The yearly conversion rate of patients from MCI to AD is 10–15%, although conversion back to normal is possible in a small percentage. Early diagnosis of AD is important in an attempt to intervene or slow the advancement of the disease. Early AD (EAD) is a stage following MCI and characterized by full blown dementia; however, information involving EAD is limited. Oxidative stress is well established in MCI and AD, including protein oxidation. Protein nitration also is an important oxidative modification observed in MCI and AD, and proteomic analysis from our laboratory identified nitrated proteins in both MCI and AD. Therefore, in the current study, a proteomics approach was used to identify nitrated brain proteins in the inferior parietal lobule from four subjects with EAD. Eight proteins were found to be significantly nitrated in EAD: peroxiredoxin 2, triose phosphate isomerase, glutamate dehydrogenase, neuropolypeptide h3, phosphoglycerate mutase1, H+ -transporting ATPase, α-enolase, and fructose-1,6-bisphosphate aldolase. Many of these proteins are also nitrated in MCI and late stage AD, making this study the first to our knowledge to link nitrated proteins in stages of AD. These results are discussed in terms of potential involvement in the progression of this dementing disorder.
doi:10.1111/j.1582-4934.2008.00478.x
PMCID: PMC2819643  PMID: 18752637
protein nitration; early Alzheimer’s disease; oxidative stress; proteomics
18.  Quantitative Changes in the Mitochondrial Proteome from Subjects with Mild Cognitive Impairment, Early Stage and Late Stage Alzheimer’s disease 
The major barrier to treating or preventing Alzheimer’s disease (AD) is its unknown etiology/pathogenesis. Although increasing evidence supports a role for mitochondrial dysfunction in the pathogenesis of AD, there have been few studies that simultaneously evaluate changes in multiple mitochondrial proteins. To evaluate changes in suites of potentially interacting mitochondrial proteins, we applied 2-dimensional liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and the isotope coded affinity tag (ICAT) method to identify and quantify proteins in mitochondrial enriched fractions isolated from short postmortem interval temporal pole specimens from subjects with mild cognitive impairment (MCI, 4 subjects pooled), early Alzheimer’s disease (EAD, 4 subjects pooled), late-stage AD (LAD, 8 subjects pooled) and age-matched normal control (NC, 7 subjects pooled) subjects. A total of 112 unique, non-redundant proteins were identified and quantified in common to all three stages of disease progression. Overall, patterns of protein change suggest activation of mitochondrial pathways that include proteins responsible for transport and utilization of ATP. These proteins include adenine nucleotide translocase (ADT1), voltage dependent anion channels (VDACs), hexokinase (HXK1) and creatine kinase (KCRU). Comparison of protein changes throughout the progression of AD suggests the most pronounced changes occur in EAD mitochondria.
doi:10.3233/JAD-2010-1254
PMCID: PMC2905865  PMID: 20061648
19.  Brains with Medial Temporal Lobe Neurofibrillary Tangles But No Neuritic Amyloid Plaques Are a Diagnostic Dilemma But May Have Pathogenetic Aspects Distinct from Alzheimer Disease 
Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak Stages III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the “amyloid cascade hypothesis” of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP− cases, we analyzed 26 NFT+/NP− patient brains identified from the University of Kentucky AD Center autopsy cohort (n = 502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had neurofibrillary tangles in the medulla oblongata. Aberrant TAR-DNA binding protein-43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer’s Coordinating Center Registry (n = 5,108) and found 219 NFT+/NP− cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918–1919 pandemic. This observation may link the pathogenesis in NFT+/NP− cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.
doi:10.1097/NEN.0b013e3181aacbe9
PMCID: PMC2725359  PMID: 19535994
Alzheimer disease; Amyloid; CERAD; Neurofibrillary tangle, Postencephalitic; tau
20.  Neuropathology of Nondemented Aging: Presumptive Evidence for Preclinical Alzheimer Disease 
Neurobiology of aging  2009;30(7):1026-1036.
Objective
To determine the frequency and possible cognitive effect of histological Alzheimer’s disease (AD) in autopsied older nondemented individuals.
Design
Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer’s Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions.
Setting
Washington University Alzheimer’s Disease Research Center.
Participants
Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years).
Results
About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs.
Conclusions
Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology.
doi:10.1016/j.neurobiolaging.2009.04.002
PMCID: PMC2737680  PMID: 19376612
preclinical Alzheimer’s disease; nondemented aging; neuropathological Alzheimer’s disease
21.  Organo-Selenium (Sel-Plex) decreases amyloid burden and RNA and DNA oxidative damage in APP/PS1 mice 
Free radical biology & medicine  2009;46(11):1527-1533.
To evaluate potential antioxidant characteristics of organic selenium (Se), double knock-in transgenic mice expressing human mutations for the amyloid precursor protein (APP) and human presenilin-1 (PS-1) were provided a Se-deficient diet, a Se-enriched (Sel-Plex), or a control diet from 4 to 9 months of age followed by a control diet until 12 months of age. Levels of DNA, RNA, and protein oxidation as well as lipid peroxidation markers were determined in all mice and amyloid beta peptide (Aβ) plaques were quantified. APP/PS1 mice provided Sel-Plex showed significantly (P < 0.05) lower levels of Aβ plaque deposition and significantly decreased levels of DNA and RNA oxidation. Sel-Plex-treated mice showed no significant differences in levels of lipid peroxidation or protein oxidation compared to APP/PS1 mice on a control diet. To determine if diminished oxidative damage was associated with increased antioxidant enzyme activities, brain glutathione peroxidase (GSH-Px), glutathione reductase, and glutathione transferase activites were measured. Sel-Plex-treated mice showed a modest but significant increase in GSH-Px activity compared to mice on a normal diet (P< 0.5). Overall, these data suggest that organic Se can reduce Aβ burden and minimize DNA and RNA oxidation and support a role for it as a potential therapeutic agent in neurologic disorders with increased oxidative stress.
doi:10.1016/j.freeradbiomed.2009.03.008
PMCID: PMC2683469  PMID: 19303433
Alzheimer’s disease; DNA oxidation; RNA oxidation; organo-selenium; antioxidants
22.  Evidence that γ-Secretase Mediates Oxidative Stress-Induced β-Secretase Expression in Alzheimer's Disease 
Neurobiology of aging  2008;31(6):917-925.
β-secretase (BACE1), an enzyme responsible for the production of amyloid β-peptide (Aβ), is increased by oxidative stress and is elevated in the brains of patients with sporadic Alzheimer's disease (AD). Here we show that oxidative stress fails to induce BACE1 expression in presenilin-1 (γ-secretase)-deficient cells and in normal cells treated with γ-secretase inhibitors. Oxidative stress-induced β-secretase activity and sAPPβ levels were suppressed by γ-secretase inhibitors. Levels of γ- and β-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE1 level in the brains of 3xTgAD mice was reduced by treatment with a γ-secretase inhibitor. Our findings suggest that γ-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive Aβ production in AD.
doi:10.1016/j.neurobiolaging.2008.07.003
PMCID: PMC2858254  PMID: 18687504
β-secretase; Alzheimer's disease; oxidative stress; γ-secretase
23.  Neuropathologic Alterations in Mild Cognitive Impairment: A Review 
Mild cognitive impairment (MCI), the earliest clinically detectable phase of the trajectory toward dementia and Alzheimer’s disease (AD), catalyzed the desire for even earlier detection and prevention of AD. Although it is a clinical diagnosis, its underlying neuropathological findings are just being defined. MCI is best studied in longitudinally followed patients in centers that are experienced in dementing disorders. In this review of the few major clinical-pathological reports of longitudinally followed patients, it appears that most autopsied amnestic MCI (aMCI) patients are on a pathway toward AD. Neurofibrillary pathology in entorhinal cortex, hippocampus, and amygdala – not amyloid plaques – is the major substrate for aMCI and for memory decline. In addition, many MCI patients have other concomitant pathological alterations, the most common of which are strokes, but also include argyrophilic grains and Lewy bodies. These findings are not surprising because most MCI autopsied cases have been in the older (80 to 90 year) range where these findings are common. In early AD, the phase following MCI, the significant change is an increase in neurofibrillary tangles in the neocortex that correlates with an increase in Braak score and the observed clinical progression.
doi:10.3233/JAD-2010-1220
PMCID: PMC2872776  PMID: 20061641
Alzheimer’s disease; mild cognitive impairment; neurofibrillary tangles; preclinical Alzheimer’s disease
24.  Modeling the Association between 43 Different Clinical and Pathological Variables and the Severity of Cognitive Impairment in a Large Autopsy Cohort of Elderly Persons 
We evaluated the association between mini-mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression-based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimer’s disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high-functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP-43-related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.
doi:10.1111/j.1750-3639.2008.00244.x
PMCID: PMC2864342  PMID: 19021630
ApoE; cognition; human; stroke; DLB; hippocampal sclerosis
25.  Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease 
Omega-3 fatty acids are essential for brain growth and development. They play an important role throughout life, as critical modulators of neuronal function and regulation of oxidative stress mechanisms, in brain health and disease. Docosahexanoic acid (DHA), the major omega-3 fatty acid found in neurons, has taken on a central role as a target for therapeutic intervention in Alzheimer’s disease (AD). A plethora of in vitro, animal model, and human data, gathered over the past decade, highlight the important role DHA may play in the development of a variety of neurological and psychiatric disorders, including AD. Cross sectional and prospective cohort data have demonstrated that reduced dietary intake or low brain levels of DHA are associated with accelerated cognitive decline or the development of incipient dementia, including AD. Several clinical trials investigating the effects of omega-3 fatty acid supplementation in AD have been completed and all failed to demonstrate its efficacy in the treatment of AD. However, these trials produced intriguing data suggesting that the beneficial effects of omega-3 fatty acid supplementation may depend on the stage of disease, other dietary mediators, and apolipoprotein E status.
PMCID: PMC2854051  PMID: 20396634
Alzheimer’s disease; omega-3 fatty acids; oxidative stress; clinical studies; treatment

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