Conserved reduction of m⁶A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts

N⁶-methyladenosine (m⁶A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m⁶A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m⁶A epitranscriptome of the hippocampal subregions CA1, CA3, and the dentate gyrus and the anterior cingulate cortex (ACC) in young and aged mice. We observed a decrease in m⁶A levels in aged animals. Comparative analysis of cingulate cortex (CC) brain tissue from cognitively intact human subjects and Alzheimer's disease (AD) patients showed decreased m⁶A RNA methylation in AD patients. m⁶A changes common to brains of aged mice and AD patients were found in transcripts linked to synaptic function including calcium/calmodulin-dependent protein kinase 2 (CAMKII) and AMPA-selective glutamate receptor 1 (Glua1). We used proximity ligation assays to show that reduced m⁶A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m⁶A levels impaired synaptic function. Our results suggest that m⁶A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.