ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid‐β Pathology
Amyloid-beta (Aβ) aggregation, mitochondrial dysfunction, and cognitive decline are hallmarks of Alzheimer's disease (AD), but its initiating molecular events remain unknown. Given that RNA modifications regulate neurodevelopment and neurodegeneration, we explore their functional role in 5xFAD mice, an Aβ AD model. We discover that N1-methyladenosine (m1A) is the most altered RNA modification, and that its regulator demethylase, ALKBH3 is upregulated. Strikingly, Alkbh3 reduction decreases Aβ plaques and restores cognition. Conversely, elevated ALKBH3 levels, observed in AD patients, compromise neuronal morphology and mitochondrial function by impairing mitophagy (degradation of dysfunctional mitochondria), a known driver of neuronal dysfunction. Mechanistically, we reveal that ALKBH3 removes m1A from PINK1 mRNA, the mitophagy master regulator. Given that ALKBH3 is elevated in human AD, causally linked to mitophagy impairment, and confers neuroprotection when depleted, we present ALKBH3 as a mechanistically validated therapeutic target in AD.
Authors
- Francesco Faiola (ORCID: https://orcid.org/0000-0002-3512-8253)
- Shuchen Yang
- Mingjie Dong
- Tiezhan Lu
- Liang Xue (ORCID: https://orcid.org/0000-0003-3606-4615)
- Jingfeng Zhou
- Ping Luo (ORCID: https://orcid.org/0000-0002-0039-747X)
- Y Li (ORCID: https://orcid.org/0009-0004-0961-0777)
- Yuxuan Shui
- Magdalena J. Koziol (ORCID: https://orcid.org/0000-0002-4123-4343)
- Ke Lü (ORCID: https://orcid.org/0000-0002-0029-7874)
- Na Yin (ORCID: https://orcid.org/0000-0001-6758-8935)
- Waleed Alam (ORCID: https://orcid.org/0000-0001-8622-4985)
- Yuying Wang (ORCID: https://orcid.org/0009-0000-3482-4110)
- Lei Zhang (ORCID: https://orcid.org/0000-0002-0952-3057)
- Xinliang Zhang (ORCID: https://orcid.org/0000-0001-8513-3328)
- You Peng (ORCID: https://orcid.org/0000-0002-8738-171X)
- Fei Zhao (ORCID: https://orcid.org/0000-0003-2878-425X)
- Yali He
- S. M. Yu
- Zilong Gao
- Meng Bao
- Yi Zhou
- Peiming Li
- Jiajia Li
- Wuyunhan Ma
Institutions
- Capital Medical University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Beijing Normal University (CN)
- Beijing Tian Tan Hospital (CN)
- Chinese Institute for Brain Research (CN)
- Research Center for Eco-Environmental Sciences (CN)
- University of Chinese Academy of Sciences (CN)
- China Agricultural University (CN)
- University of Pennsylvania (US)
Publication Details
- Journal
- Advanced Science
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1002/advs.202522572
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00