The amyloid p-protein (Afi) is closely linked to the pathophysiological processes that lead to Alzheimer disease (AD), and likely are ultimately responsible for the neural system collapse that causes the clinical syndrome of dementia. However the mechanistic role of Afi and the form in which it is toxic remain controversial. One hypothesis is that the insoluble amyloid plaque itself is deleterious to the brain. Contrasting this argument is the hypothesis that the damage is caused by soluble Aft oligomers. The overall goal of his Project is to examine these two competing hypotheses critically and determine whether one or both are more likely. In this research plan, we propose three specific aims built around advances in biochemical and morphological techniques. To learn whether and how soluble A(3oligomers, monomers and/or plaque cores correlate with the histopathological changes (gliosis, Ap deposits, neurofibrillary tangles), we will quantify the levels of soluble oligomers and monomers by new Size Exclusion Chromatography and sensitive IP/Western techniques and correlate these findings with each subject's detailed neuropathological phenotype and with clinical information. A second approach to these questions will utilize a newly developed histological preparation that allows visualization of individual synaptic elements, fibrillar Ap, and oligomeric Ap simultaneously. We have observed that oligomeric Ap-directed antibodies reveal a """"""""halo"""""""" around plaques that corresponds to the region around plaques that have diminished dendritic spine density. Furthermore, oligomeric Ap-directed antibodies demonstrate puncta that co-localize with PSD95 positive dendritic spines. These observations motivate an analysis of oligomeric Apand synaptic change that will take aim at fundamental mechanisms of Ap-associated synaptic loss. These studies will address a central unresolved question: how do soluble oligomeric forms relate to the fibrillar, histologically detected forms of Ap. Moreover, our experiments will also directly address whether Ap in cognitively normal controls who have Ap deposits differ from those in subjects with AD. By taking advantage of well characterized material from the MADRC Neuropathology Core's Brain Bank, Clinical Core evaluations, and Statistical Core expertise, we plan to test hypotheses directed at the relationship of Ap to cognitive impairment and neuronal toxicity.

Public Health Relevance

Project 3 of the Massachusetts ADRC will test the competing hypotheses of the role of Ap protein and the form in which its toxicity is associated with cognitive dysfunction and Alzheimer's disease neuropathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005134-28
Application #
8235897
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
28
Fiscal Year
2011
Total Cost
$213,070
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Mattos, Meghan K; Snitz, Beth E; Lingler, Jennifer H et al. (2017) Older Rural- and Urban-Dwelling Appalachian Adults With Mild Cognitive Impairment. J Rural Health 33:208-216
Moga, Daniela C; Abner, Erin L; Wu, Qishan et al. (2017) Bladder antimuscarinics and cognitive decline in elderly patients. Alzheimers Dement (N Y) 3:139-148
Wachinger, Christian; Reuter, Martin; Klein, Tassilo (2017) DeepNAT: Deep convolutional neural network for segmenting neuroanatomy. Neuroimage :
Sennik, Simrin; Schweizer, Tom A; Fischer, Corinne E et al. (2017) Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data. J Alzheimers Dis 55:1519-1528
Marquié, Marta; Verwer, Eline E; Meltzer, Avery C et al. (2017) Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case. Acta Neuropathol Commun 5:75
Wang, Zemin; Jackson, Rosemary J; Hong, Wei et al. (2017) Human Brain-Derived A? Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP. J Neurosci 37:11947-11966
Liu, Ganqiang; Locascio, Joseph J; Corvol, Jean-Christophe et al. (2017) Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts. Lancet Neurol 16:620-629
Neu, Scott C; Pa, Judy; Kukull, Walter et al. (2017) Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol 74:1178-1189
Xia, Chenjie; Makaretz, Sara J; Caso, Christina et al. (2017) Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease. JAMA Neurol 74:427-436
Dickerson, Bradford C; McGinnis, Scott M; Xia, Chenjie et al. (2017) Approach to atypical Alzheimer's disease and case studies of the major subtypes. CNS Spectr 22:439-449

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