biostudies-literatureSun JNICHD NIH HHSNIA NIH HHSNIMH NIH HHS53https://www.ebi.ac.uk/biostudies/studies/S-EPMC6318289biostudies-literatureUnknown10(1)CRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage. APP N-terminus and compensatory APP-homologues remain intact, with no apparent effects on neurophysiology in vitro. Robust APP-editing is seen in human iPSC-derived neurons and mouse brains with no detectable off-target effects. Our strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic events that abrogates APP/BACE-1 convergence in this setting. Our work offers conceptual proof for a selective APP silencing strategy.Nature communicationsCRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage.PMC6318289R21 AG052404R01 MH078972R01 AG048218P50 AG033514U54 HD090256Shen MStockton MCarlson-Stevermer JDas UQiao DSproul AAWang LZhao XKoo SYJones MVSnead AMLoi JPetersen AJMcLean PJRoy SBhattacharyya ASaha KSun JDelenclos MfalseCRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage.CRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage. APP N-terminus and compensatory APP-homologues remain intact, with no apparent effects on neurophysiology in vitro. Robust APP-editing is seen in human iPSC-derived neurons and mouse brains with no detectable off-target effects. Our strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic events that abrogates APP/BACE-1 convergence in this setting. Our work offers conceptual proof for a selective APP silencing strategy.2019-01-01T00:00:00Z2019 Jan2024-11-12T18:17:46.99Z2019-03-26T22:30:04ZS-EPMC63182893060477110.1038/s41467-018-07971-8