Dissertation/Thesis Abstract

Neuroinflammation, Age, and Apoe ϵ4 Affect Aspects of the Autophagy System in Alzheimer's Disease
by Parcon, Paul A., Ph.D., University of Arkansas for Medical Sciences, 2018, 223; 10815338
Abstract (Summary)

Alzheimer’s disease (AD) is characterized by clinical dementia and the presenceof extraneuronal protein aggregates, consisting mainly of Aβ peptides in amyloid plaques, as well as intraneuronal protein aggregates, consisting of hyperphosphorylated tau in neurofibrillary tangles. While risk factors for Alzheimer’s disease are known, how they may influence the clearance of these entities by autophagy, in many cases, remains to be shown. Our study builds on past work showing the effects of age in increasing IL-1β as well as IL-1β-mediated increases in the Alzheimer risk protein ApoE as well as APP and P-tau, leading us to focus on these three risk factors: age, neuroinflammation, and APOE ϵ4. We propose that, in addition to increasing production of these toxic protein aggregates, these AD risk factors may inhibit clearance of these aggregates by negative effects on autophagy. To examine this hypothesis, we employed a multidisciplinary approach to examine aspects of autophagy in post-mortem brain tissue of patients with AD compared to age-matched controls (AMC), as well as to compare these results with cell and animal models that mimic those risk factors, such as IL-1β treatment and genetic expression of ApoE3 and ApoE4, and used computational modeling and simulations to predict testable molecular interactions. First, we characterized the composition of these protein aggregates in AD vs AMC, and then tested the effects of neuroinflammation on protein ubiquitination by studying parkin, NEDD8, and PINK1 in AD brain as well as IL-1β treated cells. Next, we compared the effects of normal aging and Alzheimer’s disease on retrograde transport in the context of APOE genotype differences by measurements of APP and retrograde motor protein complex dynein/dynactin, an important aspect of neuronal autophagy. Finally, we measured the effects of ApoE4 protein, in comparison to ApoE3, on autophagy transcription and aggregate clearance in AD patients homozygotic for APOE ϵ3,3 and APOE ϵ4,4 as well as in cells over-expressing ApoE3 or ApoE4. Our results point to autophagy dysfunction as a common mechanism of three important risk factors for AD, and could lead to directed development of therapeutics to harness autophagy function to prevent or slow progression of AD pathogenesis.

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Indexing (document details)
Advisor: Griffin, W. Sue T.
Commitee: Barger, Steven W., Crooks, Peter A., Griffin, W. Sue T., Nixon, Ralph A., Shmookler-Reis, Robert J.
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 79/10(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biology, Biochemistry, Aging
Keywords: Alzheimer's, Apoe, Autophagy, Il-1, Neuroinflammation, Parkin
Publication Number: 10815338
ISBN: 9780438037618
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