# Resilience to Alzheimer's disease by targeting adult hippocampal neurogenesis

> **NIH NIH RF1** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $2,173,794

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD), the most common form of age-related dementia, is characterized by cognitive
impairment, neurodegeneration, β-amyloid (Aβ) deposition, and neurofibrillary tangle (NFT) formation. Adult
hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons
in the adult hippocampus, remains strong in healthy human brains but drops steeply in AD patients, even before
the presence of Aβ plaques and NFTs. On the other hand, adult-born neurons are significantly more abundant
in non-demented individuals with AD neuropathology (resilient). AHN levels correlate with cognitive function in
AD and mild cognitive impairment patients. Using Aβ-overexpressing 5×FAD mice, we identified AHN as a
primary event that mediates AD pathogenesis when impaired, and as a potential treatment strategy for AD when
enhanced in combination with elevating brain-derived neurotrophic factor (BDNF). Increasing either AHN or
BDNF alone was not sufficient to ameliorate cognitive dysfunction. We hypothesize that stimulating both AHN
and BDNF could serve as a brain resilience enhancing strategy to slow AD. Further study on how AHN and
BDNF cooperate and on how AHN is preserved in resilient brains is required to assess their role as therapeutic
agents to treat cognitive decline in AD. The objective of this proposal is to rigorously test our hypothesis using
mechanistic molecular and cellular techniques, bioinformatics integration, morphological and functional studies,
and behavioral testing. We will achieve our objective by exploring the mechanism(s) by which AHN cooperates
with BDNF and by testing whether our strategy to improve cognition by increasing both AHN and BDNF can be
generalized in tauopathy (Aim 1); by performing integrative single-cell transcriptomic analysis of AHN in AD and
resilient human brains, mouse models, and iPSC-derived neuronal cell models (Aim 2); and by testing the
therapeutic potential of newly-identified pharmacological/natural compounds that trigger AHN and BDNF in AD
(Aim 3). A successful therapy would ideally both remove those pathological hallmarks of AD (e.g., Aβ and tau
pathologies, neuroinflammation, and cell loss) and provide a level of functional recovery. Thus, we will test
whether increasing AHN, in part, could be a potentially powerful adjunct therapeutic for AD that provides
functional recovery.

## Key facts

- **NIH application ID:** 10983913
- **Project number:** 1RF1AG085291-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** SE HOON CHOI
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,173,794
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10983913

## Citation

> US National Institutes of Health, RePORTER application 10983913, Resilience to Alzheimer's disease by targeting adult hippocampal neurogenesis (1RF1AG085291-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10983913. Licensed CC0.

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