# Exosomes:From biogenesis and secretion to the early pathogenesis of Alzheimer's disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

ABSTRACT
Bi-directional communication between astrocytes and neurons regulates synaptic formation, synaptic strength,
and participates in the regulation of neural circuitry by coordinating activity among groups of neurons.
Astrocyte dysfunction in Alzheimer’s (AD), and other neurodegenerative conditions has been postulated to
contribute to perturbations in activity of neural networks involved in memory and executive functions. Although
AD associated modifications in the composition and quantity of various cytokine, chemokine and growth factors
released from astrocytes have been demonstrated, these observations have thus far been insufficient to
explain how astrocyte stress contributes to neuronal dysfunction. Advancements in our understanding of the
biology of extracellular vesicles have begun to implicate glial released microvesicles as primary mediators of
glia to neuron communication. In preliminary experiments we provide evidence that a variety of stimuli can
induce astrocytes to shed microvesicles. The molecular cargo of these astrocyte-shed microvesicles was
complex, and contained more than 200 distinct proteins, 100 miRNA, and hundreds of bioreactive lipid species.
Moreover, the protein, miRNA and lipid composition of astrocyte exosomes was modified by the stimulus used
to induce release and could be further modified by pre-treatment with oligomeric A peptides. These astrocyte-
shed exosomes directly interacted with neurons to modify neuronal structure and function. Based on these
preliminary findings we reasoned that a scientific focus on any one protein, lipid or miRNA would be unlikely to
produce a true representation of the functions regulated by this complex signaling vesicles. Therefore, we used
bioinformatic and systems biology approaches to understand how the protein, miRNA and lipid composition of
exosomes interacts to regulate neuronal signaling pathways identified by whole genome sequencing of target
neurons. In this application we focused our efforts on a small number of the identified pathways. In particular
we concentrated on neural pathways associated with synapse formation, spine formation, and neurite
outgrowth, as these neuronal structures are damaged in AD. The goals of this application are to understand
how endogenous excitatory stimuli and inflammatory stimuli associated with AD modulate the cargo of
astrocyte-shed exosomes and how these exosomes regulate/dysregulate the structure and function of target
neurons.

## Key facts

- **NIH application ID:** 9931096
- **Project number:** 5R01AG057420-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Norman J Haughey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931096

## Citation

> US National Institutes of Health, RePORTER application 9931096, Exosomes:From biogenesis and secretion to the early pathogenesis of Alzheimer's disease (5R01AG057420-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9931096. Licensed CC0.

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