载脂蛋白E
诱导多能干细胞
生物
表型
神经科学
阿尔茨海默病
等位基因
神经元
基因
细胞生物学
疾病
内科学
遗传学
医学
胚胎干细胞
作者
Chengzhong Wang,Ramsey Najm,Qin Xu,Dah-Eun Jeong,David W. Walker,Maureen E. Balestra,Seo Yeon Yoon,Heidi Yuan,Gang Li,Zachary A. Miller,Bruce L. Miller,Mary J. Malloy,Yadong Huang
出处
期刊:Nature Medicine
[Springer Nature]
日期:2018-04-09
卷期号:24 (5): 647-657
被引量:259
标识
DOI:10.1038/s41591-018-0004-z
摘要
Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD. Human iPSC-derived neurons are generated from individuals with or without Alzheimer's disease carrying different APOE alleles and reveal a toxic, neuron-intrinsic gain of function of the ApoE4 variant that is a strong genetic risk factor for AD.
科研通智能强力驱动
Strongly Powered by AbleSci AI