Microglia and astrocyte activation is region‐dependent in the α‐synuclein mouse model of Parkinson's disease

• Published in: Glia Vol. 71; no. 3; pp. 571 - 587
• Main Authors: Basurco, Leyre, Abellanas, Miguel Angel, Ayerra, Leyre, Conde, Enrique, Vinueza‐Gavilanes, Rodrigo, Luquin, Esther, Vales, Africa, Vilas, Amaya, Martin‐Uriz, Patxi San, Tamayo, Ibon, Alonso, Marta M., Hernaez, Mikel, Gonzalez‐Aseguinolaza, Gloria, Clavero, Pedro, Mengual, Elisa, Arrasate, Montserrat, Hervás‐Stubbs, Sandra, Aymerich, Maria S.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.03.2023; Wiley Subscription Services, Inc
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animal models; Animals; astrocyte; Astrocytes; Astrocytes - metabolism; Basal ganglia; CD11b antigen; Cell density; Central nervous system diseases; Cytology; Degeneration; Dopamine receptors; Gene sequencing; Immune system; Inflammation; Macrophages; Mesencephalon; Mesencephalon - metabolism; Mice; Microglia; Microglia - metabolism; Monocytes; Movement disorders; myeloid; Myeloid cells; Neostriatum; Neurodegeneration; Neurodegenerative Diseases; Neuroprotection; Parkinson Disease - genetics; Parkinson's disease; Phagocytes; Phagocytosis; Substantia nigra; Synuclein; Viruses; synuclein; Parkinson's disease; myeloid; inflammation; neurodegeneration; astrocyte; microglia
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24295

Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro‐inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno‐associated virus serotype 9 expressing the α‐synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+) and astrocytes (ACSA2+) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti‐inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro‐inflammatory state and were similar to disease‐associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro‐inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α‐synuclein‐dependent degeneration, microglia and astrocytes experience context‐dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration. Main Points Myeloid cells adopt an anti‐inflammatory phenotype in the midbrain and a pro‐inflammatory profile in the striatum of α‐synuclein‐overexpressing mice. Astrocytes in the midbrain of α‐synuclein mice are involved in the pro‐inflammatory reaction.