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- Title
CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage.
- Authors
Sun, Jichao; Carlson-Stevermer, Jared; Das, Utpal; Shen, Minjie; Delenclos, Marion; Snead, Amanda M.; Koo, So Yeon; Wang, Lina; Qiao, Dianhua; Loi, Jonathan; Petersen, Andrew J.; Stockton, Michael; Bhattacharyya, Anita; Jones, Mathew V.; Zhao, Xinyu; McLean, Pamela J.; Sproul, Andrew A.; Saha, Krishanu; Roy, Subhojit
- Abstract
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. Gene editing strategies are typically designed to correct mutant genes, but most neurodegenerative diseases are sporadic. Here the authors describe a strategy to selectively edit the C-terminus of APP and attenuate amyloid-β production, while upregulating neuroprotective α-cleavage.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-07971-8