Recent increases in human longevity have been accompanied by a rise in the incidence of dementia, raising an important question about how to preserve cognitive functioning in an aging population. Interestingly, a small percentage of individuals with pathological hallmarks of neurodegenerative disease are able to maintain normal cognition. The molecular mechanisms that govern this neuro-protected state remain unknown, but individuals that exhibit cognitive resilience (CgR) represent a unique source of insight into potential therapies that could preserve brain function in the face of aging and neurodegenerative disease. In both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR. To gain insight into potential modulators of this phenomenon, we began by studying the molecular changes that arise from environmental enrichment in mice. Global chromatin and transcriptomic profiling in cortical neurons led to the identification of Mef2a/c, a group of transcription factors (TFs) induced by neuronal activity. Conditional knockdown of Mef2a/c prior to enrichment blocked the cognitive enhancement typically afforded by an enriched environment. In order to assess the importance of Mef2 activity in regulating CgR in humans, we next turn to repositories of clinical and brain transcriptomic data, where we find that levels of MEF2C are positively associated with cognitive ability, and that MEF2 target genes are significantly overrepresented among the genes that are most predictive of cognition. Through single-nucleus RNA-sequencing of cortical tissue from a cohort of resilient and non-resilient individuals, we pinpoint upregulation of MEF2C and its transcriptional network in resilient individuals to a subpopulation of cortical, excitatory neurons. Finally, to determine the causal impact of Mef2 on cognition in the context of neurodegeneration, we overexpress Mef2a/c in the PS19 mouse model of tauopathy. Remarkably, Mef2 overexpression alone is sufficient to improve cognition and reduce hyperexcitability in PS19 mice. Overall, our findings reveal a novel role for MEF2 TFs in promoting cognition and cognitive resilience, highlighting their potential as novel biomarkers or therapeutic targets for healthy aging and neurodegeneration.
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