# Regulation of extracellular vesicle secretory pathways in Alzheimer's disease

> **NIH NIH P01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $279,393

## Abstract

ABSTRACT
We propose that extracellular vesicles (EV) released from compartments along the endosomal-lysosomal (EL)
pathway both reflect and contribute to the pathogenesis of Alzheimer's disease (AD). We further hypothesize
that AD-related dysfunctions in the EL pathway causing mistrafficking or preventing efficient degradation affect
exocytosis and brain EV levels. These ideas are supported by our preliminary findings showing significant
changes in the levels and content of brain EV in Down syndrome and with apolipoprotein E4 (ApoE4)
expression, both of which cause EL alterations. We will investigate the mechanism(s) of neuronal and glial
secretion of exosomes – the better understood EV subtype – by late-endosome/multivesicular bodies
(LE/MVB) and the impact of endosome dysfunction on exosome, and more broadly, EV biology. Important
mechanistic drivers of EL pathway pathology in AD that we will examine for their impact on brain EV are the β-
site cleaved carboxyl-terminal fragment of the amyloid β precursor protein (βCTF), hyperactivation of rab5, and
altered cholesterol trafficking/metabolism. Highlighting the integrative nature of this Program across the entire
EL pathway, we will examine the novel idea that lysosomal exocytosis is altered by lysosomal hydrolytic and
pH impairments associated with AD-risk factors including cholesterol perturbation, ApoE4, and loss-of-function
mutations in presenilin 1 and 2. Aim 1 will use genetic models and crosses (Core B) and a high cholesterol
diet (P1) to test in vivo the hypothesis that factors increasing endocytic drive promote EV release from the
LE/MVB, while factors promoting lysosomal dysfunction will have a greater impact on exocytic release from
lysosomes. We will characterize various brain EV types and their differential origins from neurons and glia. We
will determine the molecular mechanisms underlying altered EV secretion, changes in EV uptake, and
alterations in EV clearance from the brain in AD-relevant pathological conditions resulting from i) altered early
endosomal function (with P1) and/or ii) lysosomal dysfunction (with P2). We will examine the proteome,
lipidome (with Core C) and RNA content (with P4) of EV and of the intracellular compartments contributing to
EV generation to identify pathogenic changes altering exocytosis. In Aim 2, using direct manipulation of EV
generation and release relevant to disease mechanisms, we will identify manipulations that normalize EV
levels, testing our hypothesis that restoring EV secretion can reduce cellular pathology. As a rescue paradigm,
we will test cystatin C-derived small peptides to identify molecules with established cystatin C-like protective
effects that, in addition to augmenting EV secretion, can alleviate endosomal pathology, induce autophagy and
lysosomal degradation, and confer protection against neuronal loss and memory deficits. Thus, this Project will
define the mechanisms regulating EV generation, secretion, and their content, tes...

## Key facts

- **NIH application ID:** 10126779
- **Project number:** 5P01AG017617-20
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** EFRAT LEVY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $279,393
- **Award type:** 5
- **Project period:** 2000-02-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126779

## Citation

> US National Institutes of Health, RePORTER application 10126779, Regulation of extracellular vesicle secretory pathways in Alzheimer's disease (5P01AG017617-20). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10126779. Licensed CC0.

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