2. Academic Validation
  3. ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid-β Pathology

ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid-β Pathology

  • Adv Sci (Weinh). 2026 Jun;13(32):e22572. doi: 10.1002/advs.202522572.
Yueyang Li 1 2 3,  Sifei Yu 2 3 4,  Kaidong Lu 2 3 5,  Yujie Zhang 2 3,  Mingjie Dong 2 3,  Yan Peng 1 2 3 6,  Liang Xue 2 3 6,  Waleed Alam 2 3,  Yuxuan Shui 1 2 3,  Yi Zhou 2 3 7,  Wuyunhan Ma 2 3,  Meng Bao 2 3,  Peiming Li 2 3,  Peiyi Luo 2 3,  Tiezhan Lu 2 3,  Jiajia Li 2 3,  Kang Zhang 2 3 7,  Yuying Wang 2 3 5,  Shuchen Yang 2 3 8,  Nuoya Yin 9 10,  Francesco Faiola 9 10,  Zilong Gao 2 3,  Jingfeng Zhou 2 3 11,  Fei Zhao 2 3,  Yali He 2 3,  Magdalena J Koziol 2 3 6
Affiliations

Affiliations

  • 1 Peking University, Beijing, China.
  • 2 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3 Chinese Institute for Brain Research, Beijing, Beijing, China.
  • 4 School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 5 College of Biological Sciences, China Agricultural University, Beijing, China.
  • 6 Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing, China.
  • 7 Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 8 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 9 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
  • 10 College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, China.
  • 11 State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China.
PMID: 41816968 DOI: 10.1002/advs.202522572
Abstract

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.

Keywords

ALKBH3; Alzheimer's disease (AD); Amyloid‐β, m1A; mitochondrial; mitophagy.

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