Research squareJan 9, 2026

Reducing a Chemical Modification by Targeting METTL3 May Lower Tau Damage and Memory Loss in Alzheimer's Disease

Alzheimers & Treatments Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 10, 2026

Abstract

Significantly elevated m6A levels were found in human Alzheimer's disease frontal cortex tissue compared to healthy controls.

Increased m6A modification is associated with hyperphosphorylated tau and amyloid-β deposition in Alzheimer's disease.
Similar elevations in m6A levels were observed in a humanized tau transgenic mouse model of Alzheimer's disease.
Inhibition of the methyltransferase METTL3 with STM2457 reduced m6A levels in PS19 mice.
Treatment with STM2457 alleviated tau pathology and neurodegeneration in PS19 mice.
STM2457-treated PS19 mice demonstrated significant improvements in learning and memory compared to untreated mice.

Simplified

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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Competing interests

Declaration of Interests L.J. and A.T. have filed a patent application related to the therapeutic approach described in this manuscript (U.S. Provisional Patent Application No. 63/933,846). All other authors declare no competing interests.

PubMed

Funding Sources

NIA NIH HHS

PubMed

Reducing a Chemical Modification by Targeting METTL3 May Lower Tau Damage and Memory Loss in Alzheimer's Disease

Abstract

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Abstract

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