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Intrinsic ecto-5'-Nucleotidase/A1R Coupling may Confer Neuroprotection to the Cerebellum in Experimental Autoimmune Encephalomyelitis

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Abstract

Experimental autoimmune encephalomyelitis (EAE) is widely used animal model of multiple sclerosis (MS). The disease is characterized by demyelination and neurodegeneration triggered by infiltrated autoimmune cells and their interaction with astrocytes and microglia. While neuroinflammation is most common in the spinal cord and brainstem, it is less prevalent in the cerebellum, where it predisposes to rapid disease progression. Because the induction and progression of EAE are tightly regulated by adenosinergic signaling, in the present study we compared the adenosine-producing and -degrading enzymes, ecto-5'-nucleotidase (eN/CD73) and adenosine deaminase (ADA), as well as the expression levels of adenosine receptors A1R and A2AR subtypes in nearby areas around the fourth cerebral ventricle—the pontine tegmentum, the choroid plexus (CP), and the cerebellum. Significant differences in histopathological findings were observed between pontine tegmentum and cerebellum on the same horizontal section level. Reactive astrogliosis and massive infiltration of CD4 + cells and macrophages in CP and pontine tegmentum resulted in local demyelination. In cerebellum, there was no evidence of infiltrates, microgliosis and neuroinflammation at the same sectional level. In addition, Bergman glia showed no signs of reactive gliosis. As for adenosinergic signaling, significant upregulation of eN/CD73 was observed in all areas studied, but in association with different adenosine receptor subtypes. In CP and pons, overexpression of eN/CD73 was coupled with induction of A2AR, whereas in cerebellum, a modest increase in eN/CD73 in resident Bergman glia was accompanied by a strong induction of A1R in the same type of astrocytes. Thus, the presence of specialized astroglia and intrinsic differences in adenosinergic signaling may play a critical role in the differential regional susceptibility to EAE inflammation.

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Data Availability

Raw data were generated at Faculty of Biology University of Belgrade. Derived data supporting the findings of this study are available from the corresponding author on request.

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Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Ministry of Science, Technological Development and Innovation of Republic of Serbia, (Grant Nos. 451–03-68/2023–14/200178) and University of Defence (Grant No. MFVMA/02/24-26).

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  1. Milorad Dragic

    Present address: Laboratory for Neurobiology, Faculty of Biology, University of Belgrade, Belgrade, Serbia

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  1. Laboratory for Neurobiology, Faculty of Biology, University of Belgrade, Belgrade, Serbia

    Andjela Stekic, Dejan Stevic, Tamara Dokmanovic, Marina Anastasov, Danica Popovic, Milica Zeljkovic Jovanovic & Nadezda Nedeljkovic

  2. Medical Faculty of Military Medical Academy, University of Defense, 11 000, Belgrade, Serbia

    Jelena Stanojevic & Ivana Stevanovic

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Contributions

All authors contributed to the study conception and design. Milorad Dragic and Nadezda Nedeljkovic designed the study. Dejan Stevic, Andjela Stekic, Ivana Stevanovic, Milica Zeljkovic Jovanovic and Jelena Stanojevic participated in a preparation of brain tissue sections for histological and immunohistological study. Milorad Dragic, Andjela Stekic, Marina Anastasov, Danica Popovic and Milica Zeljkovic Jovanovic performed immunohistochemical staining, while Milorad Dragic, Dejan Stevic and Andjela Stekic performed confocal microscopy. Dejan Stevic, Andjela Stekic and Milica Zeljkovic Jovanovic prepared crude membrane fraction (P2) and preformed enzyme assays. Dejan Stevic, Ivana Stevanovic and Milica Zeljkovic Jovanovic, Tamara Dokmanovic, Marina Anastasov and Danica Popovic performed Western blotting and quantification. Milorad Dragic and Nadezda Nedeljkovic wrote the manuscript. All authors discussed and edited the manuscript and read and approved the final version.

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Correspondence to Nadezda Nedeljkovic or Milorad Dragic.

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All experimental procedures were performed in accordance with EU Directive 2010/63 and approved by the Ethics Committee for the Use of Laboratory Animals of the Faculty of Biology, University of Belgrade, Belgrade, Republic of Serbia (Application number: 119–01-4/11/2020–09).

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Stekic, A., Stevic, D., Dokmanovic, T. et al. Intrinsic ecto-5'-Nucleotidase/A1R Coupling may Confer Neuroprotection to the Cerebellum in Experimental Autoimmune Encephalomyelitis. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04174-9

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