Glial activation precedes alpha-synuclein pathology in a mouse model of Parkinson's disease. (September 2021)

• Record Type: Journal Article
• Authors: Izco, Maria; Blesa, Javier; Verona, Guglielmo; Cooper, J Mark; Alvarez-Erviti, Lydia
• Is Part Of: Neuroscience research. Volume 170(2021)
• Page Start: 330
• Page End: 340
• Publication Date: 2021-09
• Subjects: CNS Central Nervous System -- CSF Cerebrospinal fluid -- DA Dopamine -- dpi days post-injection -- GFAP glial fibrillary acidic protein -- LB Lewy bodies -- OD Optical densitometry -- PET Positron emission tomography -- PD Parkinson's disease -- SEM standard error of the mean -- SNpc Substantia nigra pars compacta -- TH Tyrosine hydroxylase -- WT Wild type -- α-syn PFF alpha-synuclein pre-formed fibrils -- α-syn alpha-synuclein; Parkinson's disease -- Mouse model -- Alpha-Synuclein -- Neuroinflammation -- Microglia -- Astrocytes; Neurosciences -- Research -- Periodicals; Neurosciences -- Research -- Japan -- Periodicals; Neurology -- Periodicals; Neurosciences -- Periodicals; Neurosciences -- Recherche -- Périodiques; Neurosciences -- Recherche -- Japon -- Périodiques; Neurosciences -- Research; Japan; Periodicals; 612.8
• DOI: 10.1016/j.neures.2020.11.004
• Languages: English
• ISSNs: 0168-0102

Abstract

Graphical abstract: Highlights: Microglial cell activation in SNpc precedes alpha-synuclein inclusion formation. In striatum a significant astrogliosis was observed 90 dpi. Alpha-synuclein monomer did not result in long-term glia activation. Neuroinflammation is an early event in PD pathogenesis. Abstract: Neuroinflammation is increasingly recognized as an important feature in the pathogenesis of Parkinson's disease (PD). However, it remains unclear whether neuroinflammation contributes to nigral degeneration in PD or is merely a secondary marker of neurodegeneration. We aimed to investigate the temporal relationship between synucleopathy, neuroinflammation and nigrostriatal degeneration in a mouse model of PD. Mice received unilateral intrastriatal injection of alpha-synuclein pre-formed fibrils, alpha-synuclein monomer or vehicle and were sacrificed at 15, 30 and 90 days post-injection. Intrastriatal inoculation of alpha-synuclein fibrils led to significant alpha-synuclein aggregation in the substantia nigra peaking at 30 days after injection while the significant increase in Iba-1 cells, GFAP cells and IL-1β expression peaked earlier at 15 days. At 90 days, the striatal dopaminergic denervation was associated with astroglial activation. Alpha-synuclein monomer did not result in long-term glia activation or increase in inflammatory markers. The spread of alpha-synuclein aggregates into the cortex was not associated with any changes to neuroinflammatory markers. Our results demonstrate that in the substantia nigra glial activation is an early event that precedes alpha-synuclein inclusion formation, suggesting neuroinflammation could play an important early role in the pathogenesis of PD.