# Contributions of cell type and exosome signaling to prodromal synaptic and circuit changes in Alzheimer's Disease models

> **NIH NIH RF1** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $2,618,631

## Abstract

Alzheimer’s Disease (AD) is characterized by loss of synapses, resulting in decline of cognitive function. The
pathology of AD is increasingly recognized to involve neuronal interactions with other brain cell types, notably
microglia and astrocytes. Extracellular vesicles (EVs) are secreted by all cells in the brain, and carry protein and
RNA cargo. EVs have the capacity to signal from donor to recipient cells within brain tissue and modify cell
functions, as shown in cancers and multiple neurological diseases. EV propagation of pathologic proteins
between cells in the brain is a strong candidate mechanism underlying at least some aspects of AD pathology,
suggesting that distinct EV cargos may not only serve as biomarkers for disease but also directly induce
vulnerability to or protection from pathologic disease states. Yet, little is known about EV cargo diversity and
bioactivity from key brain cell types implicated in AD. Furthermore, the impact of genetic susceptibility loci or
other factors such as gender has not been determined with respect to EV content, EV bioactivity or variation in
neuronal responses to EVs. To overcome these barriers, we propose to use iPSCs and direct reprogramming to
generate purified cultures of human neurons, astrocytes and microglia from iPSCs that vary by their AD-related
genetic background or expected susceptibility. Because variation at APOE has a strong effect on both AD risk
(APOE4) and protection (APOE2) we will profile EV cargos of EVs from isogenic iPSCs of each APOE genotype
using state-of-the-art proteomic and RNA-Seq methods. In parallel, we will address the functional consequences
of EV bioactivity on human induced neurons with two sensitive readouts: imaging neuronal connectivity and
synaptic dynamics and unbiased transcriptomic profiling. These collaborative studies will establish a novel
catalog of cell-type based profiles of EV cargo diversity and signaling bioactivity. Comparing EV contents from
pathologic risk and protective variants has the potential to uncover novel mechanisms related to cell-to-cell
spread of pathogenic or protective signals, and identify candidate biomarkers to test in clincal samples of human
AD patients.

## Key facts

- **NIH application ID:** 10540117
- **Project number:** 1RF1AG079517-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Kristin Kay Baldwin
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,618,631
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540117

## Citation

> US National Institutes of Health, RePORTER application 10540117, Contributions of cell type and exosome signaling to prodromal synaptic and circuit changes in Alzheimer's Disease models (1RF1AG079517-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10540117. Licensed CC0.

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