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The Arc Gene Confers Genetic Susceptibility to Alzheimer’s Disease in Han Chinese

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia. The deposition of β-amyloid (Aβ) plaques in the brain was considered one of the main neuropathological hallmarks of AD. As the loss of synapses always occurs during AD progression, AD has been gradually regarded as a “synaptopathy.” The activity-regulated cytoskeleton-associated protein (Arc) was recently identified as a key factor for AD due to its active roles in synaptic plasticity, learning, memory, and Aβ generation. However, there is little evidence to support the association of the Arc gene with AD. In this study, a two-stage case-control study of 1471 Han Chinese was conducted to investigate the genetic association between the Arc gene and AD. Variant rs10097505 in the 3′UTR region was significantly associated with AD. The whole exons of the Arc gene were also screened in 99 AD patients with a high heritability (familial and/or onset age <55 years old). One missense variant (c.20G>A, p.T7I) was identified in two AD patients but was absent in the controls from the general populations. Both rs10097505 and c.20G>A were predicted to be potentially pathogenic. Further luciferase assay, data mining, and integrative analyses revealed that the AD-risk genotype AA of rs10097505 was associated with an increased Arc mRNA expression and an elevated Aβ level. Our results indicated that the Arc gene would confer susceptibility to AD in Han Chinese, probably through changing the protein structure or affecting the Arc expression in brain tissues, which would finally contribute to the pathogenesis and development of AD.

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Acknowledgements

We thank all participants in this study. We thank Miss Hui-Zhen Wang and Qiu-Xiang Hu for technical assistance and Dr. Jirong Long for searching the Arc variant p.T7I in her unpublished dataset. This study was supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003) and the Bureau of Frontier Sciences and Education, Chinese Academy of Sciences (QYZDJ-SSW-SMC005). Data collection and sharing for this project was funded by the ADNI (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China

    Rui Bi, Li-Li Kong, Min Xu, Guo-Dong Li, Deng-Feng Zhang & Yong-Gang Yao

  2. Institute of Health Sciences, Anhui University, Hefei, Anhui, 230601, China

    Li-Li Kong & Buchang Zhang

  3. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China

    Min Xu & Guo-Dong Li

  4. The Mental Health Center and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610064, China

    Tao Li

  5. Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Yiru Fang & Chen Zhang

  6. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Yong-Gang Yao

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  1. Rui Bi
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Correspondence to Yong-Gang Yao.

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Rui Bi and Li-Li Kong contributed equally to this work.

For the Alzheimer’s Disease Neuroimaging Initiative: data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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Bi, R., Kong, LL., Xu, M. et al. The Arc Gene Confers Genetic Susceptibility to Alzheimer’s Disease in Han Chinese. Mol Neurobiol 55, 1217–1226 (2018). https://doi.org/10.1007/s12035-017-0397-6

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