PDF(Pubmed)
Abstract：
Familial Alzheimer\'s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.
摘要：
家族性阿尔茨海默病（FAD）可由编码早老素-1的PSEN1突变引起，早老素-1是裂解淀粉样前体蛋白的γ-分泌酶复合物的一种成分。钙（Ca2+）稳态和谷氨酸信号的改变与FAD的发病机制有关；然而，在人类中，很难评估这些表型是否是淀粉样蛋白或tau病理的结果。这项研究旨在通过测量带有PSEN1突变的诱导多能干细胞（iPSC）衍生的神经元对谷氨酸和离子型谷氨酸受体激动剂NMDA的Ca2反应来评估FAD的早期钙和谷氨酸表型。AMPA,和红藻氨酸与同基因对照和健康品系相比。数据显示，在早期神经元中，即使没有淀粉样蛋白和tau表型，FAD神经元对谷氨酸和AMPA的Ca2+反应增加,但不是NMDA或Kainate.一起,这表明PSEN1突变改变了Ca2+和谷氨酸信号作为FAD的早期表型。
