Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer’s Disease

TL;DR

This study shows that reducing m6A levels by inhibiting METTL3 can reduce tau pathology and cognitive decline in a mouse model of Alzheimer’s disease.

Contribution

The study demonstrates that pharmacological inhibition of METTL3 mitigates AD pathology and cognitive decline in a humanized tau transgenic mouse model.

Findings

Elevated m6A levels correlate with tau and amyloid-β pathology in human AD brain tissue and PS19 mice.

METTL3 inhibition with STM2457 reduces m6A, tau pathology, and neurodegeneration in PS19 mice.

STM2457-treated PS19 mice show improved learning and memory compared to untreated mice.

Abstract

Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer’s disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its “writer” methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.

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