# The role of activity induced exosome signaling in synaptic pathology of Alzheimer's Disease

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $446,851

## Abstract

ABSTRACT
Synaptic dysfunction represents a core pathological hallmark of Alzheimer's disease (AD). Impairments in
synapses underlie changes in the activity of neuronal circuits, which ultimately drive impaired cognition in AD.
Despite this, we currently have an incomplete understanding of how and why synapses are altered in AD
pathology. If we could advance our understanding of the underlying mechanisms that cause synaptic dysfunction
in AD, it would be a significant advancement in the overall understanding of AD. Recent evidence has suggested
that pathogenic amyloid beta and tau are enriched in extracellular vesicles and exosomes; but how these vesicles
contribute to disease progression, particularly how they affect synaptic function, is still unknown. In preliminary
studies, we provide evidence that activation of synaptic NMDA receptors triggers exosome release in neurons,
and that this process regulates the level of many synaptic proteins. Importantly, an analysis of these complex
datasets using multiple bioinformatic strategies, highlighted key protein-protein interaction networks that are
regulated by exosomes including the presence of AMPA receptors, amyloid precursor protein (APP), and tau.
Proteomic analysis of purified exosomes from stimulated neurons revealed the presence of several proteins
known to cause neurodegeneration, and it suggests that this process may have a major role in the spreading of
pathology. Inhibition of exosome synthesis in WT neurons eliminated synaptic potentiation demonstrating a
previously unknown function of exosome signaling. Analysis of purified exosomes from the brains of multiple
mouse models with AD-like pathology demonstrated an enrichment of APP and amyloid beta peptide as well as
an alteration of exosome protein cargos. Based on this evidence, we hypothesize that normal exosome signaling
is hijacked by AD pathology contributing to the synaptic dysfunction known to be prevalent in the disease. We
propose that activity-induced exosomes, which normally support synaptic strengthening, are overwhelmed by
aberrant enrichment of pathogenic molecules which results in disrupted synapses, in particular, impaired
synaptic strengthening. We plan to test this hypothesis by combining orthogonal techniques and disciplines
including electrophysiological measurement of synaptic function, non-biased proteomic approaches, and
imaging of exosome release dynamics. The proposed research has the potential to transform our understanding
of how altered activity-induced exosome signaling may contribute to synaptic dysfunction and spreading of AD-
like pathology.

## Key facts

- **NIH application ID:** 10388131
- **Project number:** 5R01AG061787-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jeffrey Nicholas Savas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $446,851
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388131

## Citation

> US National Institutes of Health, RePORTER application 10388131, The role of activity induced exosome signaling in synaptic pathology of Alzheimer's Disease (5R01AG061787-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10388131. Licensed CC0.

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