Conserved reduction of m6A marks during aging and neurodegeneration is linked to altered translation of synaptic transcripts

N6-methyladenosine (m6A) plays diverse roles in the regulation of mRNA metabolism. In the mammalian brain it has been linked to developmental processes, memory function and plasticity. However, the precise role of m6A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m6A epi-transcriptome in a tissue-specific manner. We furthermore show that m6A levels undergo massive decreases across mouse brain regions as a consequence of aging. Equally, Alzheimer’s disease in humans correlates with decreased N6-methylation in a similar population of transcripts that are linked to synaptic function and localized to synapses, such as the calcium/calmodulin-dependent kinase II (CaMKII). In line with this we show that reduced m6A levels impair synaptic protein-synthesis of CAMKII. Our results suggest that N6-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases. This data submission just includes mouse data. The CA1, CA3, DG and ACC of 20 mice (10 mice of 3 months of age and 10 of 16 months) pooled into 3 replicates per region for sequencing.