Cognitive resilience is mediated by the MEF2 network in mice and humans

Abstract

Recent increases in human longevity have been accompanied by a rise in the incidence of dementia. While a large proportion of aged individuals display pathological hallmarks of neurodegenerative disease, a small number of these individuals are able to maintain healthy cognitive function even in the presence of extensive brain pathology. 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 neurodegenerative disease. Here, we employ a two-pronged approach to dissect the mechanism underlying CgR. First, using multiple integrated repositories of clinical and brain transcriptomic data we identified individuals who maintained normal cognition despite harboring a large burden of Alzheimer's disease (AD) pathology.

We observe significant up-regulation of MEF2 family members in these resilient patients when compared to patients whose cognition declined in the presence of pathology. Second, we utilize the only existing animal model of CgR -- environmental enrichment --

to investigate the molecular mechanisms involved in the induction of resilience. Accessibility of Mef2 binding sites, and expression of Mef2 targets are significantly increased upon enrichment. Additionally, knockdown of Mef2 family members just prior to the initiation of enrichment block its cognitive benefits, demonstrating the necessity of Mef2 activity for achieving the enhanced cognitive potential afforded by enrichment. Neurons lacking Mef2 are hyperexcitable, which is also one of the earliest pathological alterations observed in AD. These results suggest a potential mechanistic link between the Mef2 transcriptional network induced by enrichment and the prevention of disease-associated hyperexcitability. To determine the causal impact of Mef2 on cognition in the context of neurodegeneration, we use a viral approach to manipulate the PS19 mouse model of tauopathy.

Remarkably, in the absence of enrichment, Mef2 overexpression alone is sufficient to improve cognition and reduce hyperexcitability in PS19 mice. Overall, our findings reveal a novel role for MEF2 transcription factors in promoting cognition throughout life, and maintaining cognitive resilience in the context of neurodegenerative disease.