Loss of age-associated increase in m(6)A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease.

Dysregulated RNA metabolism is a significant feature of Alzheimer's disease (AD), yet how post-transcriptional RNA modifications like N (6)-methyladenosine (m(6)A) are altered in AD is unknown. Here, we performed deamination adjacent to RNA modification targets (DART-seq) on human dorsolateral prefrontal cortices to assess changes in m(6)A with nucleotide resolution. In non-AD brains, m(6)A sites increased with age, predominantly within the 3'UTR of transcripts encoding tripartite synapse proteins. In contrast, AD brains lost the age-associated m(6)A site increase and exhibited global hypomethylation of transcripts, including MAPT and APP. Hypomethylated genes involved with GABAergic signaling, glutamate transport, and ubiquitin-mediated proteolysis exhibited reduced expression, connecting m(6)A to synaptic excitotoxicity and disrupted proteostasis in AD. Site-specific m(6)A levels were linked with GABRA1 expression and protein levels, but this relationship was abolished in AD. Our findings provide insight into post-transcriptional mechanisms of dysregulated RNA metabolism in AD that are related to aging and GABAergic regulation.