# Cell and Molecular Pathobiology of Alzheimer's Disease

> **NIH NIH P01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2020 · $249,884

## Abstract

ABSTRACT
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-β precursor protein (APP) gene but not Aβ. During this term, we established that LN
dysfunction critically involves the direct interaction of the β-site cleaved carboxyl-terminal fragment (βCTF)
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, βCTF and cholesterol. Project 2
(Nixon, Cuervo) addresses βCTF 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 βCTF, 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-populationspecific 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 ag...

## Key facts

- **NIH application ID:** 10154192
- **Project number:** 3P01AG017617-19S1
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** RALPH A. NIXON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,884
- **Award type:** 3
- **Project period:** 2000-02-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154192

## Citation

> US National Institutes of Health, RePORTER application 10154192, Cell and Molecular Pathobiology of Alzheimer's Disease (3P01AG017617-19S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10154192. Licensed CC0.

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