MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration.
MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration.
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DOI：
10.1126/scitranslmed.abd7695
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发表时间：
2021-11-03
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
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最近人类寿命的增加伴随着痴呆症发病率的上升，这提出了一个关于如何在老龄化人口中保持认知功能的重要问题。有趣的是，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能力。控制这种神经保护状态的分子机制仍然未知，但表现出认知弹性（CgR）的个体代表了对潜在疗法的独特见解，这些疗法可以在面对衰老和神经退行性疾病时保留大脑功能。在人类和动物模型中，生活在丰富的认知刺激环境中是已知最有效的CgR诱导剂。为了深入了解这种现象的潜在调节剂，我们首先研究了小鼠环境富集引起的分子变化。皮质神经元的整体染色质和转录组分析鉴定出Mef 2a和Mef 2c（Mef 2a/c）转录因子，已知这些转录因子由神经元活动诱导，作为神经元富集反应的潜在协调者。在富集之前有条件地敲除Mef 2a/c阻断了由富集环境提供的认知增强。为了评估Mef 2活性在调节人类CgR中的重要性，我们利用了临床和脑转录组数据库，其中我们发现MEF 2C的水平与认知能力呈正相关，并且MEF 2靶基因在最能预测认知的基因中显著过度表达。通过对来自一组弹性和非弹性个体的皮质组织进行单核RNA测序，我们将弹性个体中MEF 2C及其转录网络的上调定位于兴奋性神经元的亚群。最后，为了确定Mef 2在神经变性背景下对认知的因果影响，我们在tau蛋白病的PS19小鼠模型中过表达Mef 2a/c。值得注意的是，单独的Mef 2a/c过表达足以改善PS19小鼠的认知并降低过度兴奋性。总的来说，我们的研究结果揭示了MEF 2 TF在促进认知和认知弹性方面的新作用，突出了它们作为健康衰老和神经退行性疾病的新型生物标志物或治疗靶点的潜力。Mef 2在小鼠中慢性富集后被诱导，减少疾病相关的过度兴奋，并且是AD患者认知恢复力的特征。
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 of cortical neurons led to the identification of Mef2a and Mef2c (Mef2a/c) transcription factors, known to be induced by neuronal activity, as potential coordinators of the neuronal response to enrichment. Conditional knockdown of Mef2a/c prior to enrichment blocks the cognitive enhancement afforded by an enriched environment. In order to assess the importance of Mef2 activity in regulating CgR in humans, we utilize 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 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, Mef2a/c 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. Mef2 is induced upon chronic enrichment in mice, reduces disease-associated hyperexcitability, and is a feature of cognitive resilience in AD patients.
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影响因子：
29
作者：
Krell-Roesch J;Vemuri P;Pink A;Roberts RO;Stokin GB;Mielke MM;Christianson TJ;Knopman DS;Petersen RC;Kremers WK;Geda YE
通讯作者：
Geda YE
影响因子：
7.7
作者：
Harrington, Adam J.;Raissi, Aram;Cowan, Christopher W.
通讯作者：
Cowan, Christopher W.
影响因子：
9.8
作者：
De Jager, Philip L.;Ma, Yiyi;Bennett, David A.
通讯作者：
Bennett, David A.
影响因子：
64.8
作者：
Ataman B;Boulting GL;Harmin DA;Yang MG;Baker-Salisbury M;Yap EL;Malik AN;Mei K;Rubin AA;Spiegel I;Durresi E;Sharma N;Hu LS;Pletikos M;Griffith EC;Partlow JN;Stevens CR;Adli M;Chahrour M;Sestan N;Walsh CA;Berezovskii VK;Livingstone MS;Greenberg ME
通讯作者：
Greenberg ME
影响因子：
4.4
作者：
Gu Z;Eils R;Schlesner M;Ishaque N
通讯作者：
Ishaque N