亚历山大病是胶原纤维酸性蛋白（Glial Fibrillary Acidic Protein, GFAP）基因突变致其在星形胶质细胞中过度聚集的遗传性脑白质病，预后差，无有效治疗。前期研究表明GFAP过度聚集诱导的内质网应激后未折叠蛋白反应是其重要发病机制之一，阿米替林可降低星形胶质细胞GFAP表达。本研究利用亚历山大病患儿iPS细胞诱导的神经干细胞及野生型神经干细胞，体外诱导分化为星形胶质细胞，给予阿米替林干预，观察并比较星形胶质细胞胞体大小、突起数量、长度以及细胞凋亡，GFAP、δGFAP表达，检测未折叠蛋白反应通路分子指标PERK、ATF4、CHOP、IRE1α、sXBP1、ATF6、GRP78水平，证实阿米替林可抑制内质网应激后未折叠蛋白反应，对GFAP突变星形胶质细胞产生保护性作用及其分子学机制，为亚历山大病提供针对发病机制的干预药物，且阿米替林已上市，可进一步应用临床。

Alexander disease is the disease caused by dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene, which leads to the the excessive GFAP accumulation in the astrocytes. The prognosis of Alexander disease is so poor, and there is no effective treatment. Previous literatures and previous studies of our research group confirmed that the unfolded protein response after endoplasmic reticulum stress induced by excessive GFAP aggregation is an important pathogenesis of Alexander disease. We have proved that amitriptyline can reduce GFAP expression in astrocytes and play a protective role. In this project, we are going to explore the protective effect of amitriptyline through inhibiting the unfolded protein response after endoplasmic reticulum stress on GFAP mutant astrocytes differentiated from the neural stem cells by using iPS cells from Alexander disease patients. We try to give amitriptyline to the GFAP mutant astrocytes and wild-type astrocytes respectively, and observe the shape of cells, length and numbers of the processes, GFAP and δGFAP expression, cell apoptosis of the astrocytes, detect the molecular markers in the pathways of the unfolded protein reaction, such as PERK、ATF4、CHOP、IRE1α、sXBP1、ATF6、GRP78 to confirm that amitriptyline could have a protective effect on GFAP mutant astrocytes by inhibiting the unfolded protein response after endoplasmic reticulum stress, and thus may provide intervention drugs for the pathogenesis of Alexander's disease. Amitriptyline, already on the market, can be further applied in clinical trials of the Alexander disease.