| Summary: | Summary: Mutations in presenilin (PSEN) 1 and 2, which encode components of the γ-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 Aβ42 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 Aβ42 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 Aβ42 accumulation. Our results introduce an additional platform for analysis of neurological disease. : Availability of facile cell-based models is a challenge in the study of neurodegenerative diseases. Using CRISPR activation, Inoue et al. demonstrate that activation of the APP and/or BACE1 genes unmasks a γ-secretase carboxypeptidase deficiency in patient fibroblasts, promoting Aβ42 accumulation. Keywords: CRISPR/Cas9, synergistic activation mediator, Alzheimer’s disease, amyloid precursor protein, β-amyloid, BACE1, presenilin, fibroblast, induced neuronal cells, γ-secretase processivity
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