# Role of Ataxin-1 in BACE1 Expression and Alzheimer's Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $413,030

## Abstract

Project Summary
 Recent efforts to uncover genetic factors responsible for Alzheimer's disease (AD) have identified
dozens of associated loci. Among these, our research group previously reported ATXN1 in a family-based AD
genome-wide association study. ATXN1 has been otherwise known for to harbor mutations causing
spinocerebellar ataxia type 1, a neurodegenerative disease that primarily impairs coordinated movement. In a
cell-based study, knockdown of Ataxin-1 gene (ATXN1) expression increased amyloidogenic processing of the
amyloid precursor protein (APP) and the secretion of Aβ, the main component of senile plaques in AD brains.
In the preliminary examination of Ataxin-1 KO mice, we found Ataxin-1 regulates BACE1 expression,
selectively in AD-vulnerable brain regions. In AD mice, depletion of Ataxin-1 increased β-secretase-cleavage of
APP, Aβ deposition and gliosis in the cerebrum. Furthermore, Ataxin-1 KO impaired hippocampal
neurogenesis and axonal targeting, which are regulated by BACE1. To validate and expand upon these
findings, here, we propose to 1. Elucidate the molecular mechanism by which Ataxin-1 regulates BACE1
expression in the brain; 2. Assess the impact of Ataxin-1 loss of function on AD pathogenesis; and 3. Identify
and characterize novel AD-associated Ataxin-1 gene variants and/or mutations from AD DNA sample sets.
Specifically, for Aim 1, we will first determine whether Ataxin-1 regulates BACE1 mRNA level by affecting its
stability or by its transcription. To test this, we will employ acute brain slice cultures of Ataxin-1 KO and WT
mice, and examine the differential effects of transcriptional inhibitors on the steady-state level of BACE1 mRNA
and also measure newly synthesized BACE1 mRNA incorporating nucleotide analogs in the cultured slices.
We will then examine if Ataxin-1-interacting transcriptional factors bind to and regulate BACE1 promoter by
ChIP analysis. With regard to Aim 2, we will examine if the increased Aβ plaque load and gliosis are
maintained in APP-PS1/ATXN1-KO mice at older age (9 month). To determine if impaired hippocampal
neurogenesis and axonal targeting are caused by increased BACE1, we will generate ATXN1 −/−:BACE1 +/−
mice and examine if the two deficits are rescued, as compared to ATXN1 −/− mice. Finally, in Aim 3, we will
identify ATXN1 mutations/variants that either increase risk or confer protection for AD by analysis of
WGS/WES data of NIMH, NIA and ADNI AD DNA sample sets. For the most associated mutations/variants, we
will examine their effects on BACE1 expression and APP processing by incorporating them into the genome of
human neuronal cells via CRISPR/Cas9 technology. At the completion of the proposed study, we believe we
will provide critically needed data addressing the role of Ataxin-1 in regulating BACE1 expression while also
facilitating novel therapies aimed at targeting BACE1 to prevent and treat AD.

## Key facts

- **NIH application ID:** 10390309
- **Project number:** 5R01AG056775-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jaehong Suh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $413,030
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390309

## Citation

> US National Institutes of Health, RePORTER application 10390309, Role of Ataxin-1 in BACE1 Expression and Alzheimer's Disease (5R01AG056775-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10390309. Licensed CC0.

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