# Promoting adult hippocampal neurogenesis in Alzheimer's Disease Models

> **NIH NIH R21** · BROWN UNIVERSITY · 2021 · $450,579

## Abstract

Project Summary
Adult Hippocampal Neurogenesis (AHN) is critical for normal learning and memory and reduced
AHN is an early hallmark of Alzheimer’s Disease (AD). Thus, restoring AHN has emerged as an
attractive target for AD therapy. The accumulation of negative signals that degrade the
neurogenic niche contributes to the reduction in newborn neurons in AD and aging. BMPs are
components of the niche that negatively regulate neurogenesis and their levels are increased in
AD in humans and in mouse FAD models. We recently reported that full length MuSK harboring
its Ig3 domain, which is necessary for high affinity BMP binding, is a BMP co-receptor that
augments and shapes BMP signaling. In preliminary studies we established that MuSK is
endogenously expressed in neural stem cells (NSCs). We generated knock-in mice engineered
to constitutively express an alternatively spliced form of MuSK lacking the Ig3 domain (‘ΔIg3-
MuSK’). The animals are viable, fertile and have a normal life span. NSCs isolated from ΔIg3-
MuSK mice show impaired BMP responsiveness. Remarkably, the ΔIg3-MuSK mice exhibit over
a two-fold increase in AHN and improved hippocampal-dependent learning. These results
suggest that reducing MuSK-BMP activity by modulating MuSK alternative splicing is a potential
target for promoting AHN in AD. Importantly, such alternative splicing is expected to be
amenable to manipulation by exon-skipping antisense oligonucleotides. The recent success of
the ASO Spinraza for Spinal Muscular Atrophy has demonstrated that this class of drugs can be
highly effective in the human CNS, with a favorable pharmacokinetic and safety profile. In the
proposed experiments we will use mouse FAD models to test whether inhibition of the MuSK-
BMP pathway can promote AHN in the plaque-rich and inflammatory ‘AD environment’. To more
closely model the pathological and therapeutic landscape in humans, we will also use
conditional mutants to test whether manipulating the MuSK-BMP pathway after amyloid plaque
formation can promote AHN and improve cognition. If successful, this work will form an
important part of the rationale and impetus for a pursuing a MuSK-directed ASO therapy for AD.

## Key facts

- **NIH application ID:** 10288508
- **Project number:** 1R21AG073743-01
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** JUSTIN R. FALLON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,579
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288508

## Citation

> US National Institutes of Health, RePORTER application 10288508, Promoting adult hippocampal neurogenesis in Alzheimer's Disease Models (1R21AG073743-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288508. Licensed CC0.

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