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The Synergistic Effect Study of Lipopolysaccharide (LPS) and A53T-α-Synuclein: Intranasal LPS Exposure on the A53T-α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

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Abstract

Aging and interactions between genetic and environmental factors are believed to be involved the chronic development of Parkinson’s disease (PD). Among PD patients, abnormally aggregated α-synuclein is a major component of the Lewy body. Generally, the intranasal route is believed to be a gate way to the brain, and it assists environmental neurotoxins in entering the brain and is related to anosmia during early PD. The current study applies the chronic intranasal application of lipopolysaccharides (LPS) in 4-, 8-, 12- and 16-month-old A53T-α-synuclein (A53T-α-Syn) transgenic C57BL/6 mice at 2-day intervals for a 2-month period, for evaluating the behavioral, pathological, and biochemical changes and microglial activation in these animals. According to our results, after intranasal administration of LPS, A53T-α-Syn mice showed severe progressive anosmia, hypokinesia, selective dopaminergic (DAergic) neuronal losses, decreased striatal dopamine (DA) level, and enhanced α-synuclein accumulation within the substantia nigra (SN) in an age-dependent way. In addition, we found obvious NF-кB activation, Nurr1 inhibition, IL-1β, and TNF-α generation within the microglia of the SN. Conversely, the wild-type (WT) mice showed mild, whereas A53T-α-Syn mice had moderate PD-like changes among the old mice. This study demonstrated the synergistic effect of intranasal LPS and α-synuclein burden on PD development. Its underlying mechanism may be associated with Nurr1 inhibition within microglia and the amplification of CNS neuroinflammation. The mice with multiple factors, including aging, neuroinflammation, and α-synuclein mutation, have played a significant role in enhancing our understanding of how inflammation and α-synuclein mutation contribute to the neurodegeneration observed in PD.

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Data Availability

Data and material for the study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Shun Yu from Xuanwu Hospital of the Capital University of Medical Sciences, Beijing, China, for kindly providing the human α-synuclein antibody for immunofluorescence.

Funding

This work was supported by grants from the National Foundation of Natural Science of China (81501085); Clinical Research Program of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (JYLJ202003); Project of Biobank from Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (YBKB202120); Transverse Research Project of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (JYHX202117002); and Health Management Project of Shanghai Rehabilitation Medical Association (2022KJCX008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Qing He and Shuzhen Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Qing He, Li Wu, Mengxi Zhou, Lei Zhao, Yajing Chen, Jianren Liu & Wei Chen

  2. Institute of Neuroscience, Chinese Academy of Sciences (CAS) Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Shuzhen Zhang

  3. Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jian Wang

  4. Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Tengfei Ma & Ding Ma

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  1. Qing He
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Contributions

Conceived and designed the study: QH and CW. Performed the study: ZSZ (allocated experiments), QH, JW, TFM, and DM (performed the behavior tests and collected samples); QH and LW (prepared samples, PK treatment and HPLC); QH, MXZ, and ZL (performed immunofluorescence and Western blot); and YJC (collected data). Revised the paper for intellectual content: CW. Data statistics and analysis: QH and JW. Wrote the paper: QH, ZSZ, and JW. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianren Liu or Wei Chen.

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This study was approved by the Ethics Committee of Shanghai Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China. All experiments were conducted in accordance with the guidelines of the International Council for Laboratory Animal Science.

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He, Q., Zhang, S., Wang, J. et al. The Synergistic Effect Study of Lipopolysaccharide (LPS) and A53T-α-Synuclein: Intranasal LPS Exposure on the A53T-α-Synuclein Transgenic Mouse Model of Parkinson’s Disease. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04020-y

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