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

Author

Listed:
  • Jichao Sun

    (University of Wisconsin-Madison)

  • Jared Carlson-Stevermer

    (University of Wisconsin-Madison
    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
    University of Wisconsin-Madison)

  • Pamela J. McLean

    (Mayo Clinic Jacksonville)

  • Andrew A. Sproul

    (Columbia University Medical Center
    Columbia University Medical Center)

  • Krishanu Saha

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Subhojit Roy

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

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.

Suggested Citation

  • 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 & An, 2019. "CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07971-8
    DOI: 10.1038/s41467-018-07971-8
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