Inhibition of astrocytic adenosine receptor A2A attenuates microglial activation in a mouse model of Sandhoff disease

Neurobiology of Disease
Yasuhiro OgawaKazuhiko Oishi

Abstract

Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces β-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb-/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb-/- mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A2A receptor in the cerebral cortices of Hexb-/- mice at the later inflammatory phase. In cultured astrocytes, expression of A2A receptor could be induced by astrocyte defined medium, and then the activation of the A2A receptor induced ccl2 expression. In Hexb-/- mice, inhibition of the A2A receptor antagonized by istradefylline decreased the number of activated microglial cells a...Continue Reading

Citations

Jan 5, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Itzel G Ramírez-MorenoClaudia González-Espinosa
Sep 2, 2020·International Journal of Molecular Sciences·Andrés Felipe LealAngela Johana Espejo-Mojica
Oct 19, 2020·Molecular Neurodegeneration·Karim BelarbiMarie-Christine Chartier-Harlin
Jan 27, 2021·The Journal of Comparative Neurology·Karthik RaviArumugam R Jayakumar
Jun 1, 2021·Frontiers in Neurology·Marie J PietrowskiKevin Carvalho
Jul 2, 2021·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Yasuhiro OgawaKazuhiko Oishi

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