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

doi:10.1038/s41467-018-07971-8

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Article number	53
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07971-8
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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Sun, J., Carlson-Stevermer, J., Das, U., Shen, M., Delenclos, M., Snead, A. M., Koo, S. Y., Wang, L., Qiao, D., Loi, J., Petersen, A. J., Stockton, M., Bhattacharyya, A., Jones, M. V., Zhao, X., McLean, P. J., Sproul, A. A., Saha, K., & Roy, S. (2019). CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nature communications, 10(1), Article 53. https://doi.org/10.1038/s41467-018-07971-8

Sun, J, Carlson-Stevermer, J, Das, U, Shen, M, Delenclos, M, Snead, AM, Koo, SY, Wang, L, Qiao, D, Loi, J, Petersen, AJ, Stockton, M, Bhattacharyya, A, Jones, MV, Zhao, X, McLean, PJ, Sproul, AA, Saha, K & Roy, S 2019, 'CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage', Nature communications, vol. 10, no. 1, 53. https://doi.org/10.1038/s41467-018-07971-8

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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.",

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AU - Snead, Amanda M.

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AU - Sproul, Andrew A.

AU - Saha, Krishanu

AU - Roy, Subhojit

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

Abstract

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