Mutations in presenilin 1 and 2, which encode components of the γ-secretase complex, cause familial Alzheimer’s disease. It is hypothesized that altered γ-secretase mediated processing of the amyloid precursor protein to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. This paper describes an in vitro model system that enables analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In familial Alzheimer patient-derived fibroblast cultures, CRISPR activation of amyloid precursor protein or BACE unmasked an occult processivity defect in downstream γ-secretase -mediated carboxypeptidase cleavage of amyloid precursor protein, ultimately leading to higher Aβ42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on familial Alzheimer-mutant γ-secretase complexes, promoting CNS Aβ42 accumulation. These results introduce an additional platform for analysis of neurological disease.
Inoue K, Oliveira LMA, Abeliovich A: CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts. Cell Rep. 21(7):1727-1736 (2017); doi: 10.1016/j.celrep.2017.10.075.
