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Microbial infection promotes amyloid pathology in a mouse model of Alzheimer’s disease via modulating γ-secretase

Molecular Psychiatry (2024)Cite this article

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Abstract

Microbial infection as a type of environmental risk factors is considered to be associated with long-term increased risk of dementia, including Alzheimer’s disease (AD). AD is characterized by two neuropathologically molecular hallmarks of hyperphosphorylated tau and amyloid-β (Aβ), the latter generated by several biochemically reactive enzymes, including γ-secretase. However, how infectious risk factors contribute to pathological development of the AD core molecules remains to be addressed. In this work, we utilized a modified herpes simplex virus type 1 (mHSV-1) and found that its hippocampal infection locally promotes Aβ pathology in 5 × FAD mice, the commonly used amyloid model. Mechanistically, we identified HSV-1 membrane glycoprotein US7 (Envelope gI) that interacts with and modulates γ-secretase and consequently facilitates Aβ production. Furthermore, we presented evidence that adenovirus-associated virus-mediated locally hippocampal overexpression of the US7 aggravates Aβ pathology in 5 × FAD mice. Collectively, these findings identify a herpesviral factor regulating γ-secretase in the development and progression of AD and represent a causal molecular link between infectious pathogens and neurodegeneration.

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Fig. 1: Microbial herpesvirus infection promotes Aβ pathology in 5 × FAD mouse model.
Fig. 2: HSV-1 infection increases amyloid-β production in vitro.
Fig. 3: HSV-1 glycoprotein US7 modulates γ-secretase to facilitate Aβ production.
Fig. 4: Local overexpression of US7 via adenovirus-associated virus promotes Aβ pathology in 5 × FAD mice.

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Acknowledgements

We thank Dr. Junjie Zhang from the Wuhan University in China for providing HSV-1 strain plasmid, Dr. Xinwei Huang from the Kunming Medical University in China for offering HSV-1 strain, and Prof. Yong-Gang Yao lab from the KIZ for providing experimental instrument convenience. This work was supported by the Ministry of Science and Technology of China (2022ZD0213500), the National Natural Science Foundation of China (92369111), the National Science Foundation of Heilongjiang Province (LH2022H031), the Yunnan Fundamental Research Projects (202201AW070020, 202301AS070065), the Science and Technology Project Fund of Harbin Science and Technology Bureau (2023ZCJNS100), and the Open Project of Yunnan Key Laboratory of Biodiversity Information (BIKF22-01).

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  1. These authors contributed equally: Meng Zhao, Guanqin Ma, Xiaoxu Yan, Xiaohong Li.

Authors and Affiliations

  1. Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China

    Meng Zhao, Xiaoxu Yan, Erlin Wang & Jianxiong Zeng

  2. Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China

    Meng Zhao, Xiaoxu Yan & Xueling Ma

  3. Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China

    Guanqin Ma, Xiaohong Li, Erlin Wang, Xiang-Xiong Xu, Jie-Bin Zhao & Jianxiong Zeng

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

    Guanqin Ma, Xiang-Xiong Xu, Jie-Bin Zhao & Jianxiong Zeng

  5. Yunnan Key Laboratory of Biodiversity Information, Kunming, 650201, Yunnan, China

    Jianxiong Zeng

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All authors read and approved the final version of the manuscript. J.Z. and X.M. conceived of the research and designed the study. J.Z., M.Z., and G.M. wrote the manuscript. G.M., M.Z., X.Y., and X.L. performed the experiments. E.W., X.X.X., and J.B.Z. discussed the data. All authors commented on the manuscript.

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Correspondence to Xueling Ma or Jianxiong Zeng.

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Zhao, M., Ma, G., Yan, X. et al. Microbial infection promotes amyloid pathology in a mouse model of Alzheimer’s disease via modulating γ-secretase. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02428-5

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