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A CRISPR/Cas9 based strategy to manipulate the Alzheimer’s amyloid pathway

Jichao Sun, Jared Carlson-Stevermer, Utpal Das, Minjie Shen, Marion Delenclos, Amanda M. Snead, Lina Wang, Jonathan Loi, Andrew J Petersen, Michael Stockton, Anita Bhattacharyya, Mathew V. Jones, Andrew A. Sproul, Pamela J. McLean, Xinyu Zhao, Krishanu Saha, Subhojit Roy
doi: https://doi.org/10.1101/310193
Jichao Sun
1Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705
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Jared Carlson-Stevermer
3Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI 53706
4Wisconsin Institute for Discovery, University of Wisconsin-Madison, 330 N. Orchard, Madison, WI 53715
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Utpal Das
5Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093
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Minjie Shen
6Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705
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Marion Delenclos
7Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224
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Amanda M. Snead
8Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th St, New York, NY 10032
9Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University Medical Center, 630 W 168th St, New York, NY 10032
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Lina Wang
1Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705
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Jonathan Loi
2Department of Neuroscience, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705
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Andrew J Petersen
6Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705
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Michael Stockton
6Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705
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Anita Bhattacharyya
6Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705
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Mathew V. Jones
2Department of Neuroscience, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705
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Andrew A. Sproul
8Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th St, New York, NY 10032
9Taub Institute for Research on Alzheimer’s and the Aging Brain, Columbia University Medical Center, 630 W 168th St, New York, NY 10032
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Pamela J. McLean
7Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224
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Xinyu Zhao
2Department of Neuroscience, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705
6Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705
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Krishanu Saha
3Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI 53706
4Wisconsin Institute for Discovery, University of Wisconsin-Madison, 330 N. Orchard, Madison, WI 53715
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Subhojit Roy
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  • For correspondence: roy27@wisc.edu
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Abstract

The gradual accumulation of amyloid-β (Aβ) is a neuropathologic hallmark of Alzheimer’s disease (AD); playing a key role in disease progression. Aβ is generated by the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases, with BACE-1 (β-site APP cleaving enzyme-1) cleavage as the rate limiting step 1–3. CRISPR/Cas9 guided gene-editing is emerging as a promising tool to edit pathogenic mutations and hinder disease progression 4,5,6 However, few studies have applied this technology to neurologic diseases 7–9. Besides technical caveats such as low editing efficiency in brains and limited in vivo validation 7, the canonical approach of ‘mutation-correction’ would only be applicable to the small fraction of neurodegenerative cases that are inherited (i.e. < 10% of AD, Parkinson’s, ALS); with a new strategy needed for every gene. Moreover, feasibility of CRISPR/Cas9 as a therapeutic possibility in sporadic AD has not been explored. Here we introduce a strategy to edit endogenous APP at the extreme C-terminus and reciprocally manipulate the amyloid pathway – attenuating β-cleavage and Aβ, while up-regulating neuroprotective a-cleavage. APP N-terminus, as well as compensatory APP homologues remain intact, and key physiologic parameters remain unaffected. Robust APP-editing is seen in cell lines, cultured neurons, human embryonic stem cells/iPSC-neurons, and mouse brains. Our strategy works by limiting the physical association of APP and BACE-1, and we also delineate the mechanism that abrogates APP/BACE-1 interaction in this setting. Our work offers an innovative ‘cut and silence’ gene-editing strategy that could be a new therapeutic paradigm for AD.

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Posted April 28, 2018.
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A CRISPR/Cas9 based strategy to manipulate the Alzheimer’s amyloid pathway
Jichao Sun, Jared Carlson-Stevermer, Utpal Das, Minjie Shen, Marion Delenclos, Amanda M. Snead, Lina Wang, Jonathan Loi, Andrew J Petersen, Michael Stockton, Anita Bhattacharyya, Mathew V. Jones, Andrew A. Sproul, Pamela J. McLean, Xinyu Zhao, Krishanu Saha, Subhojit Roy
bioRxiv 310193; doi: https://doi.org/10.1101/310193
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A CRISPR/Cas9 based strategy to manipulate the Alzheimer’s amyloid pathway
Jichao Sun, Jared Carlson-Stevermer, Utpal Das, Minjie Shen, Marion Delenclos, Amanda M. Snead, Lina Wang, Jonathan Loi, Andrew J Petersen, Michael Stockton, Anita Bhattacharyya, Mathew V. Jones, Andrew A. Sproul, Pamela J. McLean, Xinyu Zhao, Krishanu Saha, Subhojit Roy
bioRxiv 310193; doi: https://doi.org/10.1101/310193

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