# Dysregulation of amyloid-β metabolism by impaired METTL3-m6A signaling in Alzheimer's Disease

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $201,250

## Abstract

Deposition of amyloid plaques is a major pathological hallmark in brains of Alzheimer’s disease (AD). Excess
accumulation of amyloid-β (Aβ), caused by increased Aβ production and impaired Aβ degradation, leads to
progressive brain degeneration in AD patients; hence reducing Aβ accumulation should be highly beneficial to
amyloid pathology in AD brain. N6-methyladenosine (m6A) methylation of RNA is the most prevalent,
abundant and conserved internal modification in eukaryotic RNAs and it influences fundamental aspects of
RNA metabolism including degradation, translation, splicing, and nuclear export. While RNA m6A
dysregulation is implicated in the neurodegenerative diseases, the potential role of RNA m6A dysregulation in
Aβ metabolism (production and degradation) in AD has never been investigated. Our group reported that
neuronal METTL3-m6A reduction contributes to neurodegeneration in Alzheimer’s Disease (AD). Both
methylation profiling and a sequence-based m6A modification site predictor identified multiple m6A sites in the
mRNAs of APP, its secretases and Aβ-degrading enzymes. Our preliminary results demonstrated that
METTL3 reduction led to significantly increased Aβ level likely through modulation of Aβ metabolism genes.
Based on these studies, we hypothesized that METTL3-mediated m6A reduction modulates gene
expressions in Aβ metabolism-related pathways and contributes to the amyloid pathology of AD. We
will determine the effect of METTL3 deficiency-mediated m6A reduction on mRNA metabolisms by affecting
the decay, translation, splicing and nuclear export in primary neurons. The successful completion of this study
will provide novel mechanistic insights into Aβ accumulation and amyloid pathology in AD. Identifying a
molecular target for Aβ metabolism will offer new venue for therapeutic intervention for AD.

## Key facts

- **NIH application ID:** 10867905
- **Project number:** 1R21AG086850-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Fanpeng Zhao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $201,250
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867905

## Citation

> US National Institutes of Health, RePORTER application 10867905, Dysregulation of amyloid-β metabolism by impaired METTL3-m6A signaling in Alzheimer's Disease (1R21AG086850-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867905. Licensed CC0.

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