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

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·2019·Nature Communications
DOI 10.1038/s41467-018-07971-8PMC PMC6318289
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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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Crossref · 10.1038/s41467-018-07971-8

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  • Cultured hippocampal neurons with truncated APP gene accumulate APP on the plasma membrane and present reduced colocalization of BACE-1 and APP in endosomes, confirming a key role of the YENPTY sequence in APP internalization and Aβ production by endosomes.

    “In addition, it was shown that cultured hippocampal neurons with truncated APP gene accumulate APP on the plasma membrane and present reduced colocalization of BACE-1 and APP in endosomes, confirming a key role of the YENPTY sequence in APP internalization and Aβ production by endosomes (Sun et al., 2019).”

    From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Sun et al., 2019

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Research works printed but not linked: 36

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Metadata

Authors
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.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-01-03
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-07971-8
PMC
PMC6318289
Cited by
112
References
7
Language
en
Licence

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