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 synap-tic 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 includ-ing 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.

Automated summary

This study used methylated RNA immunoprecipitation sequencing to investigate the role of N6-methyladenosine (m6A) in synaptic plasticity during cognitive decline. It was found that m6A levels decrease in aged animals and Alzheimer's disease (AD) patients. Common m6A changes were observed in transcripts related to synaptic function, and reduced m6A levels were shown to impair synaptic protein synthesis and function. These findings suggest that m6A RNA methylation plays a role in cognitive decline associated with aging and AD.