ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid‐β Pathology
Year: 2026
Type: article
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.
Source: Advanced Science
Authors: Yueyang Li, Sifei Yu, Kaidong Lu, Yujie Zhang, Mingjie Dong, Yan Peng, Liang Xue, Waleed Alam, Yuxuan Shui, Yi Zhou, Wuyunhan Ma, Meng Bao, Peiming Li, Peiyi Luo, Tiezhan Lu, Jiajia Li, Kang Zhang, Yuying Wang, Shuchen Yang, Nuoya Yin, Francesco Faiola, Zilong Gao, Jingfeng Zhou, Fei Zhao, Yali He, Magdalena J. Koziol
Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Peking University, Chinese Institute for Brain Research, Capital Medical University, China Agricultural University, Beijing Tian Tan Hospital, University of Pennsylvania, Chinese Academy of Sciences, Research Center for Eco-Environmental Sciences, University of Chinese Academy of Sciences, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Beijing Normal University, State Key Laboratory of Cognitive Neuroscience and Learning
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,730
Award: G4003688346
OpenAlex ID: W7135043653