CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer's Disease Skin Fibroblasts

被引:19
作者
Inoue, Keiichi [1 ]
Oliveira, Luis M. A. [1 ]
Abeliovich, Asa [1 ]
机构
[1] Columbia Univ, Med Ctr, Taub Inst, Dept Pathol Cell Biol & Neurol, 650 West 168th St, New York, NY 10032 USA
关键词
PLURIPOTENT STEM-CELLS; APP INTRACELLULAR DOMAIN; AMYLOID BETA-PEPTIDES; TAU-TRANSGENIC MICE; A-BETA; PRESENILIN-1; MUTATIONS; MISSENSE MUTATIONS; NEURONS; MECHANISM; GENE;
D O I
10.1016/j.celrep.2017.10.075
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mutations in presenilin (PSEN) 1 and 2, which encode components of the g-secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Ab42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In FAD patient-derived fibroblast cultures, CRISPR activation of APP or BACE unmasked an occult processivity defect in downstream GS-mediated carboxypeptidase cleavage of APP, ultimately leading to higher Ab42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on FAD-mutant GS complexes, promoting CNS Ab42 accumulation. Our results introduce an additional platform for analysis of neurological disease.
引用
收藏
页码:1727 / 1736
页数:10
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