Our PPG renewal application addresses the cell and molecular basis of late-onset Alzheimer?s disease (AD) and explores innovative approaches toward its prevention and therapy. Our main focus is the neuronal ?Lysosomal Network? (LN), encompassing the endosomal-lysosomal (EL) pathway and autophagy, which is strongly believed to play a central role in AD pathogenesis based on mounting genetic and biochemical evidence. Our PPG was first to show LN dysfunction as being pivotal to AD development, arising at the earliest stage of disease, progressing to involve multiple EL and autophagy sites, and strongly dependent on the amyloid-? precursor protein (APP) gene but not A?. During this term, we established that LN dysfunction critically involves the direct interaction of the ?-site cleaved carboxyl-terminal fragment (?CTF) of APP with a rab5 protein complex on endosomes resulting in the pathological rab5 activation known to initiate endosome dysfunction and cause cholinergic neurodegeneration. Additionally, we showed that acidification of lysosomes requires presenilin1 (PS1) and familial AD mutations of PS1 drive LN dysfunction that promotes neuritic dystrophy, amyloidogenesis, and neurodegeneration. These findings and new PPG data support our view that AD development is multifactorial, involving diverse pathological actions on the LN by AD risk genes, including ApoE4. We now propose to test the hypothesis that key genetic and environmental risk factors for late-onset AD operate via molecular mechanisms similar to those in early-onset AD and are potentially modifiable for significant therapeutic gain. The Program consists of 3 cores and 4 highly inter-dependent projects, which comprehensively investigate all major components of the LN to define multiple mechanisms underlying LN dysfunction in AD. Project 1 (Mathews) defines mechanisms and modifiers of early endosomal trafficking and signaling mediated by ApoE4, ?CTF and cholesterol. Project 2 (Nixon, Cuervo) addresses ?CTF dysregulation of lysosomal function, including chaperone-mediated autophagy (CMA), with a mechanistic focus on defective lysosomal acidification as a key disease driver and innovative therapeutic target. Project 3 (Levy) clarifies the multi-faceted impact of LN dysfunction on the release of extracellular vesicles from multiple LN organelles in neurons or glia and the potential for therapeutic modulation. Project 4 (Ginsberg, Nixon) examines in vivo LN function in homogeneous neuronal populations as influenced by ?CTF, rab5, and ApoE4 and the role of calorie restriction (CR) and CR mimetics as therapeutic modifiers of LN dysfunction via an hypothesized enhancement of autophagy flux. Tight programmatic integration is enhanced by innovative cell-population- specific transcriptomic and bioinformatic approaches, neuron- and glial specific autophagy reporter mice, and novel transgenic and KO mice enabling for the first time evaluations of rab5 and CMA in vivo in relation to AD and aging. The Program is expected to yield new insights relevant to late-onset AD and its treatment.

Public Health Relevance

This proposal addresses the molecular basis of late-onset Alzheimer?s disease (AD), the most common form of dementia, and investigates innovative approaches toward its prevention and therapy. Our focus is on the pathways in brain cells that receive and distribute nutrients from outside the cell as well as digest and recycle the unneeded materials and other cellular waste that accumulates during aging. Substantial evidence indicates that early and progressive disruption of these cellular functions plays a central role in AD development and represents a prime target for innovative therapies for AD, as intensively explored in this Program.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017617-17
Application #
9462008
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2000-02-15
Project End
2022-03-31
Budget Start
2018-05-01
Budget End
2019-03-31
Support Year
17
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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