Recent increases in human longevity have been accompanied by a rise in the incidence of dementia, highlighting the need to preserve cognitive function in an aging population. A small percentage of individuals with pathological hallmarks of neurodegenerative disease are able to maintain normal cognition. Although the molecular mechanisms that govern this neuroprotection remain unknown, individuals that exhibit cognitive resilience (CgR) represent a unique source of therapeutic insight. For both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR. To understand potential drivers of this phenomenon, we began by profiling the molecular changes that arise from environmental enrichment in mice, which led to the identification of MEF2 transcription factors (TFs). We next turned to repositories of human clinical and brain transcriptomic data, where we found that the MEF2 transcriptional network was overrepresented among genes that are most predictive of end-stage cognition. Through single-nucleus RNA sequencing of cortical tissue from resilient and nonresilient individuals, we further confirmed up-regulation of MEF2C in resilient individuals to a subpopulation of excitatory neurons. Last, to determine the causal impact of MEF2 on cognition in the context of neurodegeneration, we overexpressed Mef2a/c in the PS19 mouse model of tauopathy and found that this was sufficient to improve cognitive flexibility and reduce hyperexcitability. Overall, our findings reveal a previously unappreciated role for MEF2 TFs in promoting CgR, highlighting their potential as biomarkers or therapeutic targets for neurodegeneration and healthy aging.

中文翻译：

---

MEF2 是认知潜能的关键调节剂，并赋予神经退行性变的弹性

最近人类寿命的延长伴随着痴呆症发病率的上升，凸显了保持老龄化人口认知功能的必要性。一小部分具有神经退行性疾病病理特征的个体能够保持正常的认知。尽管控制这种神经保护的分子机制仍然未知，但表现出认知弹性 (CgR) 的个体代表了治疗洞察力的独特来源。对于人类和动物模型而言，生活在丰富的、认知刺激的环境中是已知最有效的 CgR 诱导剂。为了解这种现象的潜在驱动因素，我们首先分析了小鼠环境富集引起的分子变化，从而确定了 MEF2 转录因子 (TF)。我们接下来转向人类临床和大脑转录组数据的存储库，我们发现 MEF2 转录网络在最能预测终末期认知的基因中过多。通过对弹性和非弹性个体的皮层组织进行单核 RNA 测序，我们进一步证实了弹性个体中 MEF2C 对兴奋性神经元亚群的上调。最后，为了确定 MEF2 对神经变性背景下认知的因果影响，我们过度表达了 我们进一步证实了 MEF2C 在弹性个体中对兴奋性神经元亚群的上调。最后，为了确定 MEF2 对神经变性背景下认知的因果影响，我们过度表达了 我们进一步证实了 MEF2C 在弹性个体中对兴奋性神经元亚群的上调。最后，为了确定 MEF2 对神经变性背景下认知的因果影响，我们过度表达了Mef2a/c在 PS19 tau蛋白病小鼠模型中，发现这足以提高认知灵活性并降低过度兴奋性。总的来说，我们的研究结果揭示了 MEF2 转录因子在促进 CgR 方面以前未被重视的作用，突出了它们作为神经变性和健康衰老的生物标志物或治疗靶点的潜力。