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ABCA7-Associated Clinical Features and Molecular Mechanisms in Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common type of neurodegenerative disease and its pathogenesis is still unclear. Genetic factors are thought to account for a large proportion of the overall AD phenotypes. ATP-binding cassette transporter A7 (ABCA7) is one of the most important risk gene for AD. Multiple forms of ABCA7 variants significantly increase the risk of AD, such as single-nucleotide polymorphisms, premature termination codon variants, missense variants, variable number tandem repeat, mutations, and alternative splicing. AD patients with ABCA7 variants usually exhibit typical clinical and pathological features of traditional AD with a wide age of onset range. ABCA7 variants can alter ABCA7 protein expression levels and protein structure to affect protein functions such as abnormal lipid metabolism, amyloid precursor protein (APP) processing, and immune cell function. Specifically, ABCA7 deficiency can cause neuronal apoptosis by inducing endoplasmic reticulum stress through the PERK/eIF2α pathway. Second, ABCA7 deficiency can increase Aβ production by upregulating the SREBP2/BACE1 pathway and promoting APP endocytosis. In addition, the ability of microglia to phagocytose and degrade Aβ is destroyed by ABCA7 deficiency, leading to reduced clearance of Aβ. Finally, disturbance of lipid metabolism may also be an important method by which ABCA7 variants influence the incidence rate of AD. In the future, more attention should be given to different ABCA7 variants and ABCA7 targeted therapies for AD.

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Funding

The authors gratefully acknowledge the financial supports by National Natural Science Foundation of China [81971014] and Shanghai Municipal Commission of Health and Family Planning [20184Y0056].

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Authors and Affiliations

  1. Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiao-hang Qian & Hui-dong Tang

  2. Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiao-hang Qian & Hui-dong Tang

  3. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiao-hang Qian & Si-yue Chen

  4. Department of Neurology, Shanghai University of Medicine and Health Sciences Affiliated Sixth People’s Hospital South Campus, Shanghai, China

    Xiao-li Liu

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  1. Xiao-hang Qian
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  2. Si-yue Chen
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Contributions

Tang HD and Liu XL designed the study and prepared the manuscript. Qian XH and Chen SY summarized the research progress. All of the authors discussed the results and approved the manuscript.

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Correspondence to Xiao-li Liu or Hui-dong Tang.

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Qian, Xh., Chen, Sy., Liu, Xl. et al. ABCA7-Associated Clinical Features and Molecular Mechanisms in Alzheimer’s Disease. Mol Neurobiol 60, 5548–5556 (2023). https://doi.org/10.1007/s12035-023-03414-8

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