# Cell and Molecular Pathobiology of Alzheimer's Disease

> **NIH NIH P01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $2,424,969

## 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, CTF 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-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 a...

## Key facts

- **NIH application ID:** 10126770
- **Project number:** 5P01AG017617-20
- **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:** 2021
- **Award amount:** $2,424,969
- **Award type:** 5
- **Project period:** 2000-02-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126770

## Citation

> US National Institutes of Health, RePORTER application 10126770, Cell and Molecular Pathobiology of Alzheimer's Disease (5P01AG017617-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126770. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*