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Published February 2022 | Supplemental Material
Journal Article Open

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


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.

Additional Information

© 2021 Nature Publishing Group. Received 10 March 2020; Accepted 08 June 2021; Published 26 July 2021. 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.)). 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. These authors contributed equally: Yangyang Duan, Tao Ye. Author 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. The authors declare no competing interests. Peer review information: Nature Biomedical Engineering thanks Brandon Harvey, Brigitte van Zundert and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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August 22, 2023
December 22, 2023