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首页> 外文期刊>Aging cell. >Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model
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Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

机译：介入小鼠模型中行为和生理缺陷的表观遗传治疗

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Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD-like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7?months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.
机译：表观遗传异常涉及与认知缺陷相关的神经变性疾病，例如阿尔茨海默病（AD）。 AD的常见特征是由高渗韧带组成的神经纤维缠结的积累。表达突变体P301S人TAU蛋白的转基因小鼠发育广告样的渐进性TAU病理和认知障碍。在这里，我们表明，P301S Tau小鼠（5-7个月）的前额叶皮质（PFC）（5-7岁）的前额叶皮质（PFC）显着升高了Quchrom族组蛋白 - 赖氨酸N-甲基转移酶2（EHMT2），导致抑制组蛋白标记增加H3K9ME2，通过用选择性EHMT抑制剂UNC0642治疗逆转。行为测定表明，UNC0642治疗诱导P301S TAU小鼠的空间和识别记忆缺陷的稳健救援。同时，P301S Tau小鼠中的PFC神经元兴奋性和谷氨酰胺突触突触率降低也通过UNC0642治疗标准化。此外，EHMT抑制显着衰减P301S Tau小鼠PFC中的高磷酸化TAU水平。转录组分析显示，P301s Tau小鼠的UNC0642治疗在P301s Tau小鼠中归一化了PFC中的许多失餐基因，其富含细胞骨架和细胞外基质组织，离子通道和转运蛋白，受体信号和应力反应。这些数据表明，靶向组蛋白甲基化酶以调节基因表达可用于治疗与薄部介质相关的神经变性疾病中的认知和突触缺陷。

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