Loss of age-associated increase in m6A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease

Abstract

INTRODUCTION: Dysregulated RNA metabolism is a significant feature of Alzheimers disease (AD), yet how post-transcriptional RNA modifications like N6-methyladenosine (m6A) are altered in AD is unknown. METHODS: Here, we performed deamination adjacent to RNA modification targets (DART-seq) on human dorsolateral prefrontal cortices to assess changes in m6A with nucleotide resolution. RESULTS: In non-AD brains, m6A sites increased with age, predominantly within the 3UTR of transcripts encoding tripartite synapse proteins. In contrast, AD brains lost the age-associated m6A site increase and exhibited hypomethylation of transcripts overall, including MAPT. Hypomethylated genes were involved with GABAergic signaling, glutamate transport, and ubiquitin-mediated proteolysis exhibited reduced expression, connecting m6A to synaptic excitotoxicity and disrupted proteostasis in AD. Site-specific m6A levels were linked with GABRA1 expression and protein levels, but this relationship was abolished in AD. DISCUSSION: Our findings provide insight into post-transcriptional features of dysregulated RNA metabolism in AD that are related to aging and GABAergic regulation.