# Dysregulation of Multivesicular Body and Exosome Flux in Alzheimer's Disease

> **NIH NIH RF1** · EMORY UNIVERSITY · 2021 · $2,118,687

## Abstract

Alzheimer's disease (AD) is a progressive and degenerative disorder of the brain. It is pathologically
characterized by amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs), and loss of neurons. The key events
driving the pathogenesis in AD are not completely understood. The long-term objective of my research is to
understand the molecular and cellular processes by which neurons respond to stress and how dysfunction of
these responsive mechanisms contributes to neurodegenerative process. We propose to investigate a new
molecular regulator of exosome biogenesis and its role in AD pathogenesis. Exosomes are extracellular
microvesicles secreted by cells. Exosomes carry cargos including proteins, lipids, and RNAs to influence or
alter the phenotype of the target cells. Exosomes may spread toxic molecules related to AD such as Aβ, APP,
and tau. Modulating the level of exosomes has been shown to alter the load of Aβ plaques. Some of the basic
components involved in exosome biogenesis are known and highly related to the endocytic pathway. The
intraluminal vesicles (ILVs) of multivesicular bodies (MVBs) are the cellular source of exosomes. As MVBs fuse
with the plasma membrane, ILVs are released into the extracellular space as exosomes. In contrast to studies
on exosome cargos in AD, little is known if and how exosome biogenic machinery itself may be altered in
response to the AD related pathogenic stress. We have studied the endosomal-lysosomal pathways including
autophagy in neural stress response and their roles in neurodegenerative diseases, particularly AD and
Parkinson's disease. With these efforts, we have unexpectedly discovered a novel role for vacuole membrane
protein 1 (VMP1), which was previously shown to regulate autophagy peripheral cells, in exosome biogenesis
in neural cells and its involvement in AD. Our preliminary findings support strongly the new hypothesis that
VMP1 regulates the flux of MVB-exosome and -lysosome network in neurons. AD-associated pathogenic
stress increases VMP1 to promote exosome biogenesis, and this impacts the ability of donor and recipient
neurons to handle stress. We propose to use molecular as well as cellular approaches, AD transgenic animal,
and postmortem human specimens to determine in Aim I whether VMP1 controls the flux of endosomal and
lysosomal network and exosome biogenesis in neurons, and its underlying molecular mechanisms; in Aim II
whether VMP1-mediated regulation of exosome biogenesis is altered in neurons under AD associated
pathogenic stress; in Aim III whether dysregulation of VMP1-mediated exosome biogenesis occurs and
underlies neuronal stress and pathology in a transgenic rat model of AD; and in Aim IV the status of VMP1
pathway in postmortem human AD brains. The study will significantly advance our understanding of the
molecular mechanisms regulating exosome formation and reveal how the exosome biogenic process is
targeted by AD associated stressors and its involvement in AD pathogenesis.

## Key facts

- **NIH application ID:** 10213490
- **Project number:** 1RF1AG069253-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ZIXU MAO
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,118,687
- **Award type:** 1
- **Project period:** 2021-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213490

## Citation

> US National Institutes of Health, RePORTER application 10213490, Dysregulation of Multivesicular Body and Exosome Flux in Alzheimer's Disease (1RF1AG069253-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213490. Licensed CC0.

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