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Astragaloside IV Inhibits Rotenone-Induced α-syn Presentation and the CD4 T-Cell Immune Response

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Abstract

The increased α-synuclein (α-syn)-dependent activation of CD4 T cells leads to the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD). Astragaloside IV (AS-IV) protects DA neurons against neuroinflammation. The effects of AS-IV on CD4 T-cell-mediated immune responses in PD remain unknown. Rotenone (ROT) injected unilaterally into the substantia nigra pars compacta (SNc) of rats induced PD. AS-IV (20 mg/kg) was intraperitoneally injected once a day for 14 days. The limb hanging test and rotarod test were performed to evaluate the alteration of behavior at 4 and 6 weeks. Total gastrointestinal transit tests were performed at 4 weeks. Western blotting was used to detect the expression of proinflammatory cytokine proteins. Immunofluorescence staining was conducted to test the expression and localization of major histocompatibility complex class II (MHCII), cleaved caspase-1 and α-syn in astrocytes. Flow cytometry analysis, immunohistochemistry and immunofluorescence staining were used to measure the expression of CD4 T-cell subsets in the SN. The application of AS-IV protected against the loss of DA neurons and behavioral deficits in ROT-induced PD rat models. AS-IV administration inhibited the aggregation of α-syn in DA neurons and the expression of proinflammatory cytokines such as TNF-α, IL-18, IL-6 and IL-1β. AS-IV decreased the activation of CD4 T cells and three CD4 T-cell subsets: Tfh, Treg and Th1. AS-IV interrupted the ROT-induced interaction between astrocytes and CD4 T cells and the colocalization of MHCII and α-syn in astrocytes. AS-IV inhibited the expression of α-syn in astrocytes and the colocalization of α-syn and cleaved caspase-1 in astrocytes. AS-IV prevents the loss of DA neurons in PD by inhibiting the activation of α-syn-specific CD4 T cells, which is regulated by MHCII-mediated antigen presentation in astrocytes.

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Data Availability

The data used during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to Dr. Wang hongcai for technical support. We thank Medical Research Center of Binzhou Medical University Hospital for providing the high-precision experimental instruments.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (81601108), Natural Science Foundation of Shandong Province of China (ZR2016HQ14 and ZR2021MH135).

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Author notes

  1. Mengdi Wang and Fengjiao Sun contributed equally.

Authors and Affiliations

  1. Department of Neurology, Binzhou Medical University Hospital, No. 661, the 2nd Yellow River Road, Shandong Province, 256603, Binzhou City, China

    Mengdi Wang, Xiaofeng Han, Yalan liu, Jinfeng Cai, Shanshan Tong, Rui Wang & Hongcai Wang

  2. Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, China

    Fengjiao Sun & Nan Wang

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  1. Mengdi Wang
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Contributions

Mengdi Wang and Hongcai Wang conceived and designed research. Mengdi Wang, Fengjiao Sun, Xiaofeng Han, Nan Wang, Yalan Liu, Jinfeng Cai, Shanshan Tong and Rui Wang performed the experiments. Mengdi Wang, Yalan Liu, Jinfeng Cai and Shanshan Tong analyzed and interpreted the data. Mengdi Wang and Hongcai Wang wrote the manuscript, which was read, edited, and approved by all the authors. Mengdi Wang, Fengjiao Sun, Nan Wang and Hongcai Wang contributed reagents, materials, and analysis tools. All authors read and approved the final manuscript.

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Correspondence to Hongcai Wang.

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Wang, M., Sun, F., Han, X. et al. Astragaloside IV Inhibits Rotenone-Induced α-syn Presentation and the CD4 T-Cell Immune Response. Mol Neurobiol 61, 252–265 (2024). https://doi.org/10.1007/s12035-023-03566-7

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