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 and Subhojit Roy ()
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Jichao Sun: University of Wisconsin-Madison
Jared Carlson-Stevermer: University of Wisconsin-Madison
Utpal Das: University of California
Minjie Shen: University of Wisconsin-Madison
Marion Delenclos: Mayo Clinic Jacksonville
Amanda M. Snead: Columbia University Medical Center
So Yeon Koo: Columbia University Medical Center
Lina Wang: University of Wisconsin-Madison
Dianhua Qiao: University of Wisconsin-Madison
Jonathan Loi: University of Wisconsin-Madison
Andrew J. Petersen: University of Wisconsin-Madison
Michael Stockton: University of Wisconsin-Madison
Anita Bhattacharyya: University of Wisconsin-Madison
Mathew V. Jones: University of Wisconsin-Madison
Xinyu Zhao: University of Wisconsin-Madison
Pamela J. McLean: Mayo Clinic Jacksonville
Andrew A. Sproul: Columbia University Medical Center
Krishanu Saha: University of Wisconsin-Madison
Subhojit Roy: University of Wisconsin-Madison

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07971-8

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