Dysregulation of the N6-methyladenosine epitranscriptome in Alzheimer’s disease and its implications in aging, synaptic function, and RNA metabolism
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Citation
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by cognitive decline and behavioral deficits. Despite recent therapeutic advances with amyloid-β–targeting antibodies and tau antisense oligonucleotides, there remains a critical need to investigate alternative mechanisms contributing to AD. Extensive work has been done in the field of AD analyzing disease-linked changes in transcription, splicing, DNA epigenetics and chromatic structure. Altered RNA metabolism is also well documented in AD, with increased aggregation of RNA-binding proteins. However, the epigenetics of RNA are only beginning to be studied in AD. N6-methyladenosine (m6A) is the most common epigenetic modification of mRNA and a key determinant of mRNA fate, including synaptic localization and activity-dependent translation. The site-specific regulation of m6A in the cognitively normal or AD brain has yet to be determined. Here, we mapped the m6A epitranscriptome in post-mortem human AD and Control cases using deamination adjacent to RNA modification targets and sequencing (DART-seq), an antibody-independent approach for nucleotide-resolution detection of m6A-modified sites and transcripts. DART-seq reveals a 3’ untranslated region (UTR)-enriched, age-associated increase in the number of m6A sites in Control cases, which is absent in AD cases. We hypothesize that this age-related increase in m6A labeling reflects a protective role of age-associated methylation. Instead in the AD brain, m6A-modified transcripts are globally hypomethylated. We observed a group of transcripts whose m6A methylation correlates with gene or protein expression levels; these correlations occur selectively in genes encoding astrocytic glutamate importers and GABAergic ionotropic receptors, implicating m6A in regulation of the tripartite synapse, and potentially contributing to excitotoxicity. These findings are consistent with a known imbalance between excitatory glutamatergic and inhibitory GABAergic signaling that is an important feature of AD leading to excitotoxicity, synapse loss, and disease progression. We also revealed differentially abundant m6A sites on translational stress response genes and a loss of m6A-governed transcript regulation for GABRA1, consistent with altered RNA metabolism in AD. These findings provide the first nucleotide-specific m6A landscape in the human brain, show clear changes associated with AD, and open novel therapeutic strategies, such as gene editing, to site-selectively modify m6A levels with the goal of restoring synaptic function and RNA metabolism in the AD brain.
Description
2026
License
Attribution 4.0 International