Modeling familial Alzheimer's disease with induced pluripotent stem cells

被引：457

作者：

Yagi, Takuya ^{[1
]}

Ito, Daisuke ^{[1
]}

Okada, Yohei ^{[2
,3
]}

Akamatsu, Wado ^{[2
]}

Nihei, Yoshihiro ^{[1
]}

Yoshizaki, Takahito ^{[1
]}

Yamanaka, Shinya ^{[4
]}

Okano, Hideyuki ^{[2
]}

Suzuki, Norihiro ^{[1
]}

机构：

[1] Keio Univ, Sch Med, Dept Neurol, Shinjuku Ku, Tokyo 1608582, Japan

[2] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan

[3] Keio Univ, Sch Med, Kanrinmaru Project, Shinjuku Ku, Tokyo 1608582, Japan

[4] Kyoto Univ, Ctr iPS Cell Res & Applicat, Kyoto 6068507, Japan

来源：

HUMAN MOLECULAR GENETICS | 2011年 / 20卷 / 23期

基金：

日本学术振兴会;

关键词：

AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE; A-BETA; PRESENILIN-1; MUTATIONS; RECAPITULATION; HYPOTHESIS; PEPTIDE; NOTCH; GENE;

D O I：

10.1093/hmg/ddr394

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbance. Mutations of presenilin 1 (PS1) and presenilin 2 (PS2) are causative factors for autosomal-dominant early-onset familial AD (FAD). Induced pluripotent stem cell (iPSC) technology can be used to model human disorders and provide novel opportunities to study cellular mechanisms and establish therapeutic strategies against various diseases, including neurodegenerative diseases. Here we generate iPSCs from fibroblasts of FAD patients with mutations in PS1 (A246E) and PS2 (N141I), and characterize the differentiation of these cells into neurons. We find that FAD-iPSC-derived differentiated neurons have increased amyloid beta 42 secretion, recapitulating the molecular pathogenesis of mutant presenilins. Furthermore, secretion of amyloid beta 42 from these neurons sharply responds to gamma-secretase inhibitors and modulators, indicating the potential for identification and validation of candidate drugs. Our findings demonstrate that the FAD-iPSC-derived neuron is a valid model of AD and provides an innovative strategy for the study of age-related neurodegenerative diseases.

引用

页码：4530 / 4539

页数：10

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