Conserved reduction of m(6)A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts

N(6)-methyladenosine (m(6)A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m(6)A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m(6)A 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 m(6)A 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 m(6)A RNA methylation in AD patients. m(6)A 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 m(6)A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m(6)A levels impaired synaptic function. Our results suggest that m(6)A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.