ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid‐β Pathology
Source abstract
Abstract
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: crossref · Quality: baseline
Research context
OpenAlex topics: RNA modifications and cancer · Metalloenzymes and iron-sulfur proteins · MicroRNA in disease regulation
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Peking University Beijing China
Beijing Institute for Brain Research Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
Chinese Institute for Brain Research, Beijing Beijing China
School of Basic Medical Sciences Capital Medical University Beijing China
College of Biological Sciences China Agricultural University Beijing China
Research Unit of Medical Neurobiology Chinese Academy of Medical Sciences Beijing China
Department of Neurology Beijing Tiantan Hospital Capital Medical University Beijing China
Department of Bioengineering University of Pennsylvania Philadelphia Pennsylvania USA
State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco‐Environmental Sciences Chinese Academy of Sciences Beijing China
College of Resources and Environment University of Chinese Academy of Sciences Beijing China
State Key Laboratory of Cognitive Neuroscience and Learning Beijing Normal University Beijing China
Funding
Natural Science Foundation of Beijing Municipality
References (100+)
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