Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
Veterans Affairs Western New York Healthcare System, Buffalo, NY, USA.
J Alzheimers Dis. 2019;70(4):1175-1185. doi: 10.3233/JAD-190190.
Emerging evidence suggests that epigenetic dysregulation of gene expression is one of the key molecular mechanisms of neurodegeneration and Alzheimer's disease (AD). However, little is known about the role of epigenetic dysregulation on synaptic dysfunction in humans, because of the difficulties of obtaining live human neurons. Here we generated mature human cortical neurons differentiated from human embryonic stem cells, and exposed them to amyloid-β (Aβ). We found that the histone methyltransferase, EHMT1, which catalyzes histone lysine 9 dimethylation (H3K9me2, a mark for gene repression), was significantly elevated in Aβ-treated human stem cell-derived neurons. Aβ treatment led to a significant reduction of AMPAR-mediated whole-cell current and excitatory postsynaptic current. Application of BIX01294, a selective inhibitor of EHMT1/2, restored AMPAR currents and glutamatergic synaptic transmission in Aβ-treated human cortical neurons. These results suggest that inhibition of the aberrant histone methylation is a novel approach to reverse Aβ-induced synaptic deficits in human neurons.
新出现的证据表明，基因表达的表观遗传失调是神经退行性变和阿尔茨海默病 (AD) 的关键分子机制之一。然而，由于难以获得活的人类神经元，因此对于表观遗传失调对人类突触功能障碍的作用知之甚少。在这里，我们从人类胚胎干细胞中生成了成熟的人类皮质神经元，并将其暴露于淀粉样蛋白-β (Aβ) 下。我们发现，组蛋白甲基转移酶 EHMT1（催化组蛋白赖氨酸 9 二甲基化 (H3K9me2，基因抑制的标志））在 Aβ 处理的人类干细胞源性神经元中显着升高。Aβ 处理导致 AMPAR 介导的全细胞电流和兴奋性突触后电流显着降低。EHMT1/2 的选择性抑制剂 BIX01294 的应用恢复了 Aβ 处理的人类皮质神经元中的 AMPAR 电流和谷氨酸能突触传递。这些结果表明，抑制异常的组蛋白甲基化是逆转 Aβ 诱导的人类神经元突触缺陷的一种新方法。
