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1.  Bridging Integrator 1 (BIN1) Protein Expression Increases in the Alzheimer’s Disease Brain and Correlates with Neurofibrillary Tangle Pathology 
Journal of Alzheimer's disease : JAD  2014;42(4):1221-1227.
Recent genome wide association studies (GWAS) have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer’s disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (N = 71) of AD cases and controls from five different brain regions [hippocampus, inferior parietal (IP) cortex, inferior temporal (IT) cortex, frontal cortex (BA9), and superior and middle temporal gyri (SMTG)]. We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-β peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology.
PMCID: PMC4198456  PMID: 25024306
Alzheimer’s disease; myotonic dystrophy; tau; amyloid-β peptide; cellular nucleic acid binding protein; ZNF9
2.  Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity 
PLoS ONE  2014;9(11):e111899.
Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.
PMCID: PMC4229119  PMID: 25390692
3.  Alzheimer's Disease in Down Syndrome 
A key challenge to adults with Down syndrome (DS) as they age is an increased risk for cognitive decline, dementia, and Alzheimer disease (AD). In DS persons ranging from 40-49 years of age, 5.7-55% may be clinically demented and between 50-59 years, dementia prevalence ranges from 4-55% (reviewed in [1]). Despite the wide ranges reported for dementia prevalence, a consistent feature of aging in DS is the progressive accumulation of AD brain pathologies. By the age of 40 years, virtually all have sufficient senile plaques and neurofibrillary tangles for a neuropathological diagnosis of AD [2]. Thus, there is dissociation between the age of onset of AD neuropathology (40 years) and increasing signs of clinical dementia. We discuss the hypothesis that frontal impairments are a critical factor affecting cognitive function and are associated with white matter (WM) and AD neuropathology. While these may be an early sign of conversion to dementia, we also review several other clinical comorbidities that may also contribute to dementia onset.
PMCID: PMC4184282  PMID: 25285303
beta-amyloid; dementia; neurofibrillary tangles; oxidative damage; Trisomy 21
4.  Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer's Disease and Down Syndrome Dementia 
Journal of Alzheimer's disease : JAD  2010;20(0 2):S293-S310.
Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-β peptide (Aβ40 and Aβ42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with β-secretase activity and mtDNA copy number is inversely correlated with insoluble Aβ40 and Aβ42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.
PMCID: PMC4175722  PMID: 20463402
Alzheimer's disease; amyloid-β; AβPP; control region; dementia; Down syndrome; mitochondria; mitochondrial dysfunction; mtDNA
5.  Con: are we ready to translate Alzheimer’s disease-modifying therapies to people with down syndrome? 
Adults with Down syndrome develop Alzheimer’s disease neuropathology in an age-dependent manner. This unique feature provides an opportunity to test interventions targeted for prevention of Alzheimer’s disease neuropathology and dementia in Down syndrome.
In considering clinical trial designs, however, there are several challenges that we believe will be critical to examine further. These include: accuracy in dementia, mild cognitive impairment and preclinical Alzheimer’s disease diagnoses in Down syndrome; clinical trial outcome measures appropriate for individuals with Down syndrome; in vivo imaging outcome measures (and practical considerations); and contributions of medical co-morbidities to disease progression. Also, when studies are designed, the molecular target may appear to be obvious (for example, targeting beta-amyloid pathology), but chromosome 21 has over 200 additional genes that could influence both positive and negative clinical trial outcomes.
Observational longitudinal studies of aging in Down syndrome will be critically important as there is a need to establish sensitive clinical outcome measures and understand the consequences of gene overexpression in relation to specific interventions.
PMCID: PMC4255531  PMID: 25478026
6.  Rhinal and Dorsolateral Prefrontal Cortex Lesions Produce Selective Impairments in Object and Spatial Learning and Memory in Canines 
To examine the effects of rhinal and dorsolateral prefrontal cortex lesions on object and spatial recognition memory in canines, we used a protocol in which both an object (delayed non-matching to sample, or DNMS) and a spatial (delayed non-matching to position or DNMP) recognition task were administered daily. The tasks used similar procedures such that only the type of stimulus information to be remembered differed. Rhinal cortex (RC) lesions produced a selective deficit on the DNMS task, both in retention of the task rules at short delays and in object recognition memory. By contrast, performance on the DNMP task remained intact at both short and long delay intervals in RC animals. Subjects who received dorsolateral prefrontal cortex (dlPFC) lesions were impaired on a spatial task at a short, 5-sec delay, suggesting disrupted retention of the general task rules, however, this impairment was transient; long-term spatial memory performance was unaffected in dlPFC subjects. The present results provide support for the involvement of the RC in object, but not visuospatial, processing and recognition memory, whereas the dlPFC appears to mediate retention of a non-matching rule. These findings support theories of functional specialization within the medial temporal lobe and frontal cortex and suggest that rhinal and dorsolateral prefrontal cortices in canines are functionally similar to analogous regions in other mammals.
PMCID: PMC4105010  PMID: 18792072
object recognition; spatial; medial temporal lobe; entorhinal cortex; perirhinal cortex; dorsolateral prefrontal cortex; frontal lobe; canine; delayed non-matching to sample; delayed non-matching to position
7.  A Combination Cocktail Improves Spatial Attention in a Canine Model of Human Aging and Alzheimer's disease 
Journal of Alzheimer's disease : JAD  2012;32(4):1029-1042.
Alzheimer's disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of beta-amyloid (Aβ) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aβ deposits and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t(11)=4.3, p=0.001) and were more accurate across all distances (F(1,9)=20.7, p=0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and CSF Aβ were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD.
PMCID: PMC4006672  PMID: 22886019
8.  Prevention approaches in a preclinical canine model of Alzheimer’s disease: benefits and challenges 
Aged dogs spontaneously develop many features of human aging and Alzheimer’s disease (AD) including cognitive decline and neuropathology. In this review, we discuss age-dependent learning tasks, memory tasks, and functional measures that can be used in aged dogs for sensitive treatment outcome measures. Neuropathology that is linked to cognitive decline is described along with examples of treatment studies that show reduced neuropathology in aging dogs (dietary manipulations, behavioral enrichment, immunotherapy, and statins). Studies in canine show that multi-targeted approaches may be more beneficial than single pathway manipulations (e.g., antioxidants combined with behavioral enrichment). Aging canine studies show good predictive validity for human clinical trials outcomes (e.g., immunotherapy) and several interventions tested in dogs strongly support a prevention approach (e.g., immunotherapy and statins). Further, dogs are ideally suited for prevention studies as they the age because onset of cognitive decline and neuropathology strongly support longitudinal interventions that can be completed within a 3–5 year period. Disadvantages to using the canine model are that they lengthy, use labor-intensive comprehensive cognitive testing, and involve costly housing (almost as high as that of non-human primates). However, overall, using the dog as a preclinical model for testing preventive approaches for AD may complement work in rodents and non-human primates.
PMCID: PMC3968758  PMID: 24711794
antioxidant diet; atorvastatin; behavioral enrichment; beta-amyloid; combination treatment; dog; immunotherapy; statin
9.  Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer’s disease neuropathology: Redox proteomics analysis of human brain 
Biochimica et biophysica acta  2013;1832(8):1249-1259.
DS is the most frequent genetic cause of intellectual disability characterized by the anomalous presence of three copies of chromosome 21. One of the peculiar features of DS is the onset of Alzheimer’s disease neuropathology after the age of 40 years characterized by deposition of senile plaques and neurofibrillary tangles. Growing studies demonstrated that increased oxidative damage, accumulation of unfolded/damaged protein aggregates and dysfunction of intracellular degradative system are key players in neurodegenerative processes. In this study, redox proteomics approach was used to analyze the frontal cortex from DS subjects under the age of 40 compared with age-matched controls, and proteins found to be increasingly carbonylated were identified. Interestingly, our results showed that oxidative damage targets specifically different components of the intracellular quality control system such as GRP78, UCH-L1, V0-ATPase, cathepsin D and GFAP that couples with decreased activity of the proteasome and autophagosome formation observed. We also reported a slight but consistent increase of Aβ 1–42 SDS- and PBS-soluble form and tau phosphorylation in DS versus CTR. We suggest that disturbance in the proteostasis network could contribute to the accumulation of protein aggregates, such as amyloid deposits and NFTs, which occur very early in DS. It is likely that a sub-optimal functioning of degradative systems occur in DS neurons, which in turn provide the basis for further accumulation of toxic protein aggregates. The results of this study suggest that oxidation of protein members of the proteostatis network is an early event in DS and might contribute to neurodegenerative phenomena.
PMCID: PMC3940071  PMID: 23603808
Down syndrome; Oxidative stress; Autophagy; Proteasome; Alzheimer disease; Trisomy 21
10.  A canine model of human aging and Alzheimer's disease☆ 
Biochimica et biophysica acta  2013;1832(9):1384-1389.
The aged dog naturally develops cognitive decline in many different domains (including learning and memory) but also exhibits human-like individual variability in the aging process. The neurobiological basis for cognitive dysfunction may be related to structural changes that reflect neurodegeneration. Molecular cascades that contribute to degeneration in the aging dog brain include the progressive accumulation of beta-amyloid (Aβ) in diffuse plaques and in the cerebral vasculature. In addition, neuronal dysfunction occurs as a consequence of mitochondrial dysfunction and cumulative oxidative damage. In combination, the aged dog captures key features of human aging, making them particularly useful for the development of preventive or therapeutic interventions to improve aged brain function. These interventions can then be translated into human clinical trials. This article is part of a Special Issue entitled: Animal Models of Disease.
PMCID: PMC3937962  PMID: 23528711
Beagle; Beta-amyloid; Cognition; Mild cognitive impairment; Oxidative damage
11.  Early brain injury alters the blood–brain barrier phenotype in parallel with β-amyloid and cognitive changes in adulthood 
Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood–brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, β-amyloid (Aβ) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent Aβ in several brain regions of the jTBI group versus shams. In addition at 60 dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.
PMCID: PMC3564189  PMID: 23149553
amyloid; claudin 5; endothelial; juvenile; P-glycoprotein; traumatic brain injury
12.  Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines 
A long-term intervention (2.69 years) with an antioxidant diet, behavioral enrichment, or the combined treatment preserved and improved cognitive function in aged canines. While each intervention alone provided cognitive benefits, the combination treatment was additive. We evaluate the hypothesis that antioxidants, enrichment, or the combination intervention reduces age-related beta-amyloid (Aβ) neuropathology, as one mechanism mediating observed functional improvements. Measures assessed were Aβ neuropathology in plaques, biochemically extractable Aβ40 and Aβ42 species, soluble oligomeric forms of Aβ, and various proteins in the beta-amyloid precursor protein (APP) processing pathway. The strongest and most consistent effects on Aβ pathology were observed in animals receiving the combined antioxidant and enrichment treatment. Specifically, Aβ plaque load was significantly decreased in several brain regions, soluble Aβ42 was decreased selectively in the frontal cortex, and a trend for lower Aβ oligomer levels was found in the parietal cortex. Reductions in Aβ may be related to shifted APP processing towards the non-amyloidogenic pathway, as alpha-secretase enzymatic activity was increased, in the absence of changes in beta-secretase activity. While enrichment alone had no significant effects on Aβ, reduced Aβ load and plaque maturation occurred in animals receiving antioxidants as a component of treatment. AB measures did not correlate with cognitive performance on any of the 6 tasks assessed, suggesting that modulation of AB alone may be a relatively minor mechanism mediating cognitive benefits of the interventions. Overall, the data indicate that multi-domain treatments may be a valuable intervention strategy to reduce neuropathology and improve cognitive function in humans.
PMCID: PMC3769160  PMID: 20660265
antioxidant; enrichment; beta amyloid; oligomer; canine; secretase
13.  An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease 
Neurobiology of Aging  2011;33(8):1522-1532.
The endocannabinoids and their attending CB1 cannabinoid receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of post mortem brain samples from 38 Alzheimer’s disease (AD) patients and 17 control subjects, matched for age and post mortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N-arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2-arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (a) anandamide content in midfrontal cortex and scores of the Kendrick’s digit copying test (P=0.004, r=0.81; n=10), which measures speed of information processing; and (b) anandamide content in temporal cortex and scores of the Boston naming test (P=0.027, r=0.52; n=18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, Aβ42, while showing no association with Aβ40 levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ42 in APPSWE/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ42-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.
PMCID: PMC3154439  PMID: 21546126
endocannabinoid; anandamide; amyloid β42; cognitive dysfunction; Alzheimer’s disease; human brain; lipidomics
14.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
PMCID: PMC3510344  PMID: 23143602
15.  Antioxidants in the Canine Model of Human Aging 
Biochimica et Biophysica Acta  2011;1822(5):685-689.
Oxidative damage can lead to neuronal dysfunction in the brain due to modifications to proteins, lipids and DNA/RNA. In both human and canine brain, oxidative damage progressively increases with age. In the Alzheimer’s disease (AD) brain, oxidative damage is further exacerbated, possibly due to increased deposition of beta-amyloid (Aβ) peptide in senile plaques. These observations have led to the hypothesis that antioxidants may be beneficial for brain aging and AD. Aged dogs naturally develop AD-like neuropathology (Aβ) and cognitive dysfunction and are a useful animal model in which to test antioxidants. In a longitudinal study of aging beagles, a diet rich in antioxidants improved cognition, maintained cognition and reduced oxidative damage and Aβ pathology in treated animals. These data suggest that antioxidants may be beneficial for human brain aging and for AD, particularly as a preventative intervention.
PMCID: PMC3291812  PMID: 22005070
Alzheimer disease; beagle; beta-amyloid; cognition; dog; lipoic acid; vitamins
16.  Frontal Cortex Neuropathology in Dementia Pugilistica 
Journal of Neurotrauma  2012;29(6):1054-1070.
Dementia pugilistica (DP) is associated with chronic traumatic brain injury (CTBI), and leads to a “punch drunk” syndrome characterized by impairments in memory and executive function, behavioral changes, and motor signs. Microscopic features include the accumulation of neurofibrillary tangles (NFTs), beta-amyloid (Aβ), and TAR DNA binding protein 43 (TDP-43) pathology. Here we describe detailed clinical and neuropathological data about a 55-year-old retired boxer (ApoE3/4), who presented with executive dysfunction and behavioral impairments. At autopsy, significant Aβ pathology was seen, primarily in the form of diffuse plaques. Tau pathology was extensive and was determined to be of Braak and Braak stage VI. Frontal white matter showed evidence of glial tau inclusions (astrocytes and oligodendroglia). Cerebrovascular pathology was minimal with patchy amyloid angiopathy. Inflammation was another key feature, including microglial activation and significant C1q labeling of neurons, along with NFTs. TDP-43-positive pathology was also observed. Inflammation may be a key inciting as well as propagating feature of DP neuropathology.
PMCID: PMC3325552  PMID: 22017610
beta-amyloid; C1q; chronic traumatic encephalopathy; tauopathy; TDP-43
17.  Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy 
PLoS ONE  2013;8(3):e59735.
The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.
PMCID: PMC3605408  PMID: 23555764
18.  BDNF increases with behavioural enrichment and an antioxidant diet in the aged dog 
Neurobiology of Aging  2010;33(3):546-554.
The aged canine (dog) is an excellent model for investigating the neurobiological changes that underlie cognitive impairment and neurodegeneration in humans, as canines and humans undergo similar pathological and behavioural changes with aging. Recent evidence indicates that a combination of environmental enrichment and antioxidant-fortified diet can be used to reduce the rate of age-dependent neuropathology and cognitive decline in aged dogs, although the mechanisms underlying these changes have not been established. We examined the hypothesis that an increase in levels of brain-derived neurotrophic factor (BDNF) is one of the factors underlying improvements in learning and memory. Old, cognitively impaired animals that did not receive any treatment showed a significant decrease in BDNF mRNA in the temporal cortex when compared with the young group. Animals receiving either an antioxidant diet or environmental enrichment displayed intermediate levels of BDNF mRNA. However, dogs receiving both an antioxidant diet and environmental enrichment showed increased levels of BDNF mRNA when compared to untreated aged dogs, approaching levels measured in young animals. BDNF receptor TrkB mRNA levels did not differ between groups. BDNF mRNA levels were positively correlated with improved cognitive performance and inversely correlated with cortical Aβ(1–42) and Aβ(1–40) levels. These findings suggest that environmental enrichment and antioxidant diet interact to maintain brain levels of BDNF, which may lead to improved cognitive performance. This is the first demonstration in a higher animal that non-pharmacological changes in lifestyle in advanced age can up-regulate BDNF to levels approaching those in the young brain.
PMCID: PMC2935515  PMID: 20447733
Alzheimer’s disease; neurotrophin; amyloid; diet; environmental enrichment; antioxidant; mRNA
19.  Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome 
Biochimica et Biophysica Acta  2011;1822(2):130-138.
Down syndrome (DS) is the most common genetic cause of intellectual disability in children, and the number of adults with DS reaching old age is increasing. By the age of 40 years, virtually all people with DS have sufficient neuropathology for a postmortem diagnosis of Alzheimer disease (AD). Trisomy 21 in DS leads to an overexpression of many proteins, of which at least two are involved in oxidative stress and AD: superoxide dismutase 1 (SOD1) and amyloid precursor protein (APP). In this study, we tested the hypothesis that DS brains with neuropathological hallmarks of AD have more oxidative and nitrosative stress than those with DS but without significant AD pathology, as compared with similarly aged-matched non-DS controls. The frontal cortex was examined in 70 autopsy cases (n=29 control and n=41 DS). By ELISA, we quantified soluble and insoluble Aβ40 and Aβ42, as well as oligomers. Oxidative and nitrosative stress levels (protein carbonyls, HNE-bound proteins, and 3-nitrotyrosine) were measured by slot-blot. We found that soluble and insoluble Aβ and oligomers increase as a function of age in DS frontal cortex. Of the oxidative stress markers, HNE-bound proteins were increased overall in DS. Protein carbonyls were correlated with Aβ40 levels. These results suggest that oxidative damage, but not nitrosative stress, may contribute to the onset and progression of AD pathogenesis in DS. Conceivably, treatment with antioxidants may provide a point of intervention to slow pathological alterations in DS.
PMCID: PMC3260028  PMID: 22009041
Alzheimer disease; 4-hydroxy-2-nonenal; 3-nitrotyrosine; oligomers; protein carbonyl; trisomy 21
20.  Aβ aggregation profiles and shifts in APP processing favor amyloidogenesis in canines 
Neurobiology of aging  2010;33(1):108-120.
The aged canine is a higher animal model that naturally accumulates β-amyloid (Aβ) and shows age-related cognitive decline. However, profiles of Aβ accumulation in different species (40 vs. 42), its assembly states, and Aβ precursor protein (APP) processing as a function of age remain unexplored. In this study, we show that Aβ increases progressively with age as detected in extracellular plaques and biochemically extractable Aβ40 and Aβ42 species. Soluble oligomeric forms of the peptide, with specific increases in an Aβ oligomer migrating at 56kDa, also increase with age. Changes in APP processing could potentially explain why Aβ accumulates, and we show age-related shifts towards decreased total APP protein and non-amyloidogenic (α-secretase) processing coupled with increased amyloidogenic (β-secretase) cleavage of APP. Importantly, we describe Aβ pathology in the cingulate and temporal cortex and provide a description of oligomeric Aβ across the canine lifespan. Our findings are in line with observations in the human brain, suggesting that canines are a valuable higher animal model for the study of Aβ pathogenesis.
PMCID: PMC2932860  PMID: 20434811
beta amyloid; canine; dog; oligomer; abeta star; 56 kda; cingulate; temporal; secretase; app; ide; nep; ctf; adam
21.  Intersectin 1 contributes to phenotypes in vivo: implications for Down Syndrome 
Neuroreport  2011;22(15):767-772.
Intersectin 1 (ITSN1) is a chromosome 21 (HSA21) gene product encoding a multi-domain scaffold protein that functions in endocytosis, signal transduction and is implicated in Down Syndrome, Alzheimer’s Disease, and potentially other neurodegenerative diseases through activation of c-Jun N-terminal kinase (JNK). We report for the first time that ITSN1 proteins are elevated in Down Syndrome individuals of varying ages. However, ITSN1 levels decreased in aged Down Syndrome cases with Alzheimer’s Disease-like neuropathology. Analysis of a novel ITSN1 transgenic mouse reveals that ITSN1 overexpression results in a sex-dependent decrease in locomotor activity. This study reveals a link between overexpression of specific ITSN1 isoforms and behavioral phenotypes and has implications for human neurodegenerative diseases such as Down Syndrome and Alzheimer’s Disease.
PMCID: PMC3339866  PMID: 21876463
scaffold protein; MAP kinase; endocytosis; signal transduction; neurodegeneration; SH3 domain; EH domain
22.  Neurobiology of the aging dog 
Age  2010;33(3):485-496.
Aged canines naturally accumulate several types of neuropathology that may have links to cognitive decline. On a gross level, significant cortical atrophy occurs with age along with an increase in ventricular volume based on magnetic resonance imaging studies. Microscopically, there is evidence of select neuron loss and reduced neurogenesis in the hippocampus of aged dogs, an area critical for intact learning and memory. The cause of neuronal loss and dysfunction may be related to the progressive accumulation of toxic proteins, oxidative damage, cerebrovascular pathology, and changes in gene expression. For example, aged dogs naturally accumulate human-type beta-amyloid peptide, a protein critically involved with the development of Alzheimer’s disease in humans. Further, oxidative damage to proteins, DNA/RNA and lipids occurs with age in dogs. Although less well explored in the aged canine brain, neuron loss, and cerebrovascular pathology observed with age are similar to human brain aging and may also be linked to cognitive decline. Interestingly, the prefrontal cortex appears to be particularly vulnerable early in the aging process in dogs and this may be reflected in dysfunction in specific cognitive domains with age.
PMCID: PMC3168593  PMID: 20845082
Atrophy; Beagle; Beta-amyloid; Neurogenesis; Oxidative damage
23.  Coenzyme Q10 and Cognition in atorvastatin treated dogs 
Neuroscience letters  2011;501(2):92-95.
Statins have been suggested to protect against Alzheimer’s disease (AD). Recently, however, we reported that aged dogs that underwent chronic statin treatment exhibited cognitive deficits compared with age matched controls. In human studies, blood levels of Coenzyme Q10 (CoQ10) decrease with statin use. CoQ10 is important for proper mitochondrial function and is a powerful antioxidant, two important factors for cognitive health in aging. Thus, the current study tested the hypothesis that CoQ10 levels in the serum and/or parietal cortex are decreased in statin treated dogs and are associated with poorer cognition. Six aged beagles (>8 years) were administered 80 mg/day of atorvastatin for 14.5 months and compared with placebo-treated animals. As predicted, serum CoQ10 was significantly lower in statin-treated dogs. Parietal cortex CoQ10 was not different between the two groups. However, poorer cognition was correlated with lower parietal cortex CoQ10. This study in dogs suggests that serum CoQ10 is reduced with atorvastatin treatment. CoQ10 levels in brain may linked to impaired cognition in response to atorvastatin, in agreement with previous reports that statins may have a negative impact on cognition in the elderly.
PMCID: PMC3174091  PMID: 21763754
Alzheimer’s disease; Canine; Dog; Lipitor; Statins
24.  Down Syndrome and Dementia: A Randomized, Controlled Trial of Antioxidant Supplementation 
Individuals with Down syndrome over age 40 years are at risk for developing dementia of the Alzheimer type and have evidence for chronic oxidative stress. There is a paucity of treatment trials for dementia in Down syndrome in comparison to Alzheimer disease in the general (non-Down syndrome) population. This 2-year randomized, double-blind, placebo-controlled trial assessed whether daily oral antioxidant supplementation (900 IU of alpha-tocopherol, 200 mg of ascorbic acid and 600 mg of alpha-lipoic acid) was effective, safe and tolerable for 53 individuals with Down syndrome and dementia. The outcome measures comprised a battery of neuropsychological assessments administered at baseline and every 6 months. Compared to the placebo group, those individuals receiving the antioxidant supplement showed neither an improvement in cognitive functioning nor a stabilization of cognitive decline. Mean plasma levels of alpha-tocopherol increased ~2-fold in the treatment group and were consistently higher than the placebo group over the treatment period. Pill counts indicated good compliance with the regimen. No serious adverse events attributed to the treatment were noted. We conclude that antioxidant supplementation is safe, though ineffective as a treatment for dementia in individuals with Down syndrome and Alzheimer type dementia. Our findings are similar to studies of antioxidant supplementation in Alzheimer disease in the general population. The feasibility of carrying out a clinical trial for dementia in Down syndrome is demonstrated.
PMCID: PMC3410645  PMID: 21739598
Down syndrome; Alzheimer disease; antioxidants; clinical trial
25.  Dissociation of Neuropathologic Findings and Cognition 
Archives of Neurology  2007;64(8):1193-1196.
The apolipoprotein E (APOE) ε2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease.
To describe a dissociation between findings neuropathologic with normal cognition in a woman with severe Alzheimer disease with the APOE ε2/ε2 genotype.
Case report from a community based prospective study of persons 90 years or older (The 90+ Study).
A 92-year-old woman without dementia with the APOE ε2/ε2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed.
Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles.
Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits.
The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE ε2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.
PMCID: PMC3378248  PMID: 17698712

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