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Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer’s disease alleviates amyloid-related pathologies in mice

Nature Biomedical Engineering volume 6, pages 168–180 (2022)Cite this article

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Abstract

The pathology of familial Alzheimer’s disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR–Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood–brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer’s disease and other monogenic diseases that affect multiple brain regions.

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Fig. 1: Design and validation of CRISPR–Cas9-mediated genome editing to disrupt the mutant APPswe allele.
Fig. 2: Intrahippocampal AAV-mediated Cas9-SW1 editing decreases the amyloid-plaque burden in 5XFAD mice.
Fig. 3: Intrahippocampal AAV-mediated Cas9-SW1 editing decreases gliosis in 5XFAD mice.
Fig. 4: Intrahippocampal AAV-mediated Cas9-SW1 editing improves neuronal functions in 5XFAD mice.
Fig. 5: Intrahippocampal AAV-mediated delivery of Cas9-SW1 decreases pathologies associated with Alzheimer’s disease in APP/PS1 mice.
Fig. 6: Systemic delivery of AAV-PHP.eB-mediated Cas9-SW1 globally decreases amyloid-plaque burden in 5XFAD mice.
Fig. 7: Systemic delivery of AAV-PHP.eB-mediated Cas9-SW1 decreases microgliosis and neurite dystrophy, and improves cognitive performance in 5XFAD mice.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw data from whole-genome sequencing have been deposited in the NCBI Sequence Read Archive (SRA), with accession code PRJNA733582. The other raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request, as they are too large to be publicly shared.

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Acknowledgements

We thank K. Liu, W.-Y. Fu, X. Wang, K.-W. Hung, C. Kwong, R. M. Delos Reyes, K. Cheung, N. Mullapudi, E. Tam, J. Zhang, H. Cao, S.-F. Li and P.-O. Chiu of the Hong Kong University of Science and Technology; and B. E. Deverman, K. Beadle and Y. Lei of California Institute of Technology for their excellent technical assistance. We are grateful to all members of the Ip laboratory for discussions. This study was supported in part by the National Key R&D Program of China (2018YFE0203600), the Guangdong Provincial Key S&T Program (2018B030336001), the Guangdong Provincial Fund for Basic and Applied Basic Research (2019B1515130004), the Hong Kong Research Grants Council Theme-based Research Scheme (T13-605/18-W), the Area of Excellence Scheme of the University Grants Committee (AoE/M-604/16), the Innovation and Technology Commission (ITCPD/17-9), the Lee Hysan Foundation (LHF17SC01), the Shenzhen Knowledge Innovation Program (JCYJ20180507183642005 and JCYJ20200109115631248), the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions (project number: 2019SHIBS0001), the HKUST-SIAT Joint Laboratory for Brain Science for technical platform support, and the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research for technology development and broad dissemination (clover.caltech.edu (V.G.) and the CZI Neurodegeneration Challenge Network (V.G.)).

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  1. These authors contributed equally: Yangyang Duan, Tao Ye.

Authors and Affiliations

  1. Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, Center for Stem Cell Research, The Hong Kong University of Science and Technology, Hong Kong, China

    Yangyang Duan, Tao Ye, Yuewen Chen, Abigail Miranda, Xiaopu Zhou, Ka-Chun Lok, Yu Chen, Amy K. Y. Fu & Nancy Y. Ip

  2. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

    Yangyang Duan, Tao Ye, Xiaopu Zhou, Ka-Chun Lok, Yu Chen, Amy K. Y. Fu & Nancy Y. Ip

  3. Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, China

    Tao Ye, Yuewen Chen, Yu Chen, Amy K. Y. Fu & Nancy Y. Ip

  4. Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen–Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China

    Tao Ye, Yuewen Chen & Yu Chen

  5. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Zhe Qu & Viviana Gradinaru

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Contributions

Y.D., T.Y., A.K.Y.F. and N.Y.I. designed the research; Y.D., T.Y., Z.Q., A.M., X.Z., K.-C.L., Yuewen Chen and Yu Chen performed the research; Y.D., T.Y., A.K.Y.F. and N.Y.I. analysed the data; X.Z. performed bioinformatics analysis; V.G. and N.Y.I. contributed to the design and availability of reagents/analytic tools; and Y.D., T.Y., A.K.Y.F. and N.Y.I. wrote the paper with input from all authors.

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Correspondence to Nancy Y. Ip.

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Identified somatic mutations as potential off-target events.

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Duan, Y., Ye, T., Qu, Z. et al. Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer’s disease alleviates amyloid-related pathologies in mice. Nat Biomed Eng 6, 168–180 (2022). https://doi.org/10.1038/s41551-021-00759-0

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