CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage

Jichao Sun, Jared Carlson-Stevermer, Utpal Das, Minjie Shen, Marion Delenclos, Amanda M. Snead, So Yeon Koo, Lina Wang, Dianhua Qiao, Jonathan Loi, Andrew J. Petersen, Michael Stockton, Anita Bhattacharyya, Mathew V. Jones, Xinyu Zhao, Pamela J. McLean, Andrew A. Sproul, Krishanu Saha, Subhojit Roy

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Article number53
JournalNature communications
Issue number1
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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