期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 180, 期 6, 页码 2404-2416出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.02.012
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资金
- German Federal Ministry for Education and Research (BioPharma-NeuroAllianz) [0315608A, 0315608B]
- German Research Foundation [SFB645, KFO177]
- European Commission [222943]
- Hertie Foundation
- (Protein Research Unit Ruhr within Europe) State Government North Rhine-Westphalia
Alzheimer's disease (AD) is the most frequent cause of dementia. There is compelling evidence that the proteolytic processing of the amyloid precursor protein (APP) and accumulation of amyloid-beta (A beta) peptides play critical roles in AD pathogenesis. Due to limited access to human neural tissue, pathogenetic studies have, so far, mostly focused on the heterologous overexpression of mutant human APP in non-human cells. In this study, we show that key steps in proteolytic APP processing are recapitulated in neurons generated from human embryonic and induced pluripotent stem cell derived neural stem cells (NSC). These human NSC-derived neurons express the neuron-specific APP(695) splice variant, BACE1, and all members of the gamma-secretase complex. The human NSC-derived neurons also exhibit a differentiation-dependent increase in A beta secretion and respond to the pharmacotherapeutic modulation by anti-amyloidogenic compounds, such as gamma-secretase inhibitors and nonsteroidal anti-inflammatory drugs. Being highly amenable to genetic modification, human NSCs enable the study of mechanisms caused by disease-associated mutations in human neurons. Interestingly, the AD-associated PS1(L166P) variant revealed a partial loss of gamma-secretase function, resulting in the decreased production of endogenous A beta 40 and an increased A beta 42/40 ratio. The PS1(L166P) mutant is also resistant to gamma-secretase modulation by nonsteroidal anti-inflammatory drugs. Pluripotent stem cell derived neurons thus provide experimental access to key steps in AD pathogenesis and can be used to screen pharmaceutical compounds directly in a human neuronal system. (Am J Pathol 2012, 180:2404-241 http://dx.doi.org/10.1016/j.ajpath.2012.02.012)
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