Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease
Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease
复制标题
抑制 EHMT1/2 可挽救阿尔茨海默病的突触和认知功能
DOI：
10.1093/brain/awy354
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发表时间：
2019-03-01
期刊：
影响因子：
14.5
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
--
作者：
Zheng, Yan;Liu, Aiyi;Yan, Zhen
表观遗传失调会导致大脑中基因表达的改变，被认为是衰老和神经退行性变的关键病理生理学基础之一。在这里，我们发现，在晚期家族性阿尔茨海默病 (FAD) 小鼠模型中，前额皮质（阿尔茨海默病影响的关键认知区域）中赖氨酸 9 (H3K9me2) 的抑制性组蛋白 H3 二甲基化和常染色质组蛋白甲基转移酶 EHMT1 和 EHMT2 显着升高。在阿尔茨海默病患者死后组织的前额皮质区域中也检测到 H3K9me2 水平升高。与此同时，老年 FAD 小鼠前额皮质中谷氨酸受体的 H3K9me2 增加，这与 AMPA 和 NMDA 受体的转录、表达和功能减弱有关。用特异性 EHMT1/2 抑制剂治疗 FAD 小鼠可逆转组蛋白高甲基化，并导致前额皮质和海马谷氨酸受体表达和兴奋性突触功能的恢复。染色质免疫沉淀测序 (ChIP-seq) 数据表明，FAD 小鼠在参与神经元信号传导（包括谷氨酸受体）的基因中表现出全基因组 H3K9me2 富集增加，而 EHMT1/2 抑制可逆转这一现象。此外，老年FAD小鼠受损的识别记忆、工作记忆和空间记忆通过EHMT1/2抑制剂的治疗得以恢复。这些结果表明，谷氨酸受体转录的表观遗传调控被破坏是阿尔茨海默病突触和认知缺陷的基础，而针对组蛋白甲基化酶可能代表了这种流行的神经退行性疾病的一种新的治疗策略。
Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of ageing and neurodegeneration. Here we found that, in the late-stage familial Alzheimer's disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9me2) and euchromatic histone methyltransferases EHMT1 and EHMT2 were significantly elevated in the prefrontal cortex, a key cognitive region affected in Alzheimer's disease. Elevated levels of H3K9me2 were also detected in the prefrontal cortex region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9me2 at glutamate receptors was increased in prefrontal cortex of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in prefrontal cortex and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9me2 enrichment at genes involved in neuronal signalling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder.