# Molecular mechanisms underlying the preservation of neural stem cell quiescence during aging

> **NIH NIH R01** · BROWN UNIVERSITY · 2021 · $397,291

## Abstract

ABSTRACT
The R01 parent award aims to investigate the mechanisms that balance neural stem cell (NSC) quiescence
and activation during brain aging, and how disruptions in this balance result in a decline in neurogenesis with
age. In this supplement to the parent award, we will determine the extent to which activation of quiescent
NSCs is defective context of Alzheimer’s disease (AD), and discover the mechanisms responsible. Studies in
rodents have shown that activation of quiescent NSC is reduced in the aged brain, resulting in diminished
neurogenesis and hippocampus-dependent cognitive function. A number of recent reports indicate that
neurogenesis is abundant in the adult human hippocampus. Moreover, similar to rodent models, decreased
new neuron formation has been observed in healthy human aging as well as in patients with AD. While
previous studies have confirmed a sharp decline in neurogenesis in rodent AD models that recapitulates the
human condition, the mechanisms responsible remain unclear. Our overarching hypothesis is that the
activation of quiescent NSCs out of the dormant state is defective in AD, resulting in reduced
hippocampal neurogenesis. To test our hypothesis, we will use two independent methods to quantify the
quiescent NSC pool in an established mouse AD models (3xTg AD). First, we will use a label retaining
experiment to quantify the quiescent NSC pool as AD pathology progresses. Second, we will use an in vivo
assay of quiescence exit to measure activation of the NSC pool along the same timeline. To begin to discover
the mechanisms underlying the changes we observe, we will perform single-nuclei RNA-seq on FACS isolated
quiescent and activated NSCs from the mouse AD model. Successful completion of these aims will provide
novel insight into the mechanism underlying the decline in neurogenesis in AD. As a result, we expect that this
study will contribute to the discovery of new therapeutic approaches to treating Alzheimer’s and other
neurodegenerative conditions.

## Key facts

- **NIH application ID:** 10288011
- **Project number:** 3R01AG053268-05S1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Ashley E Webb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,291
- **Award type:** 3
- **Project period:** 2017-04-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288011

## Citation

> US National Institutes of Health, RePORTER application 10288011, Molecular mechanisms underlying the preservation of neural stem cell quiescence during aging (3R01AG053268-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288011. Licensed CC0.

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