Complex Deregulation and Expression of Cytokines and Mediators of the Immune Response in Parkinson's Disease Brain is Region Dependent

Abstract

Neuroinflammation is common in neurodegenerative diseases including Parkinson disease (PD). Expression of 25 mRNAs was assessed with TaqMan-PCR including members of the complement system, colony stimulating factors, Toll family, cytokines IL-8, IL-6, IL-6ST, IL-1B, TNF-α family, IL-10, TGFβ family, cathepsins and integrin family, in the substantia nigra pars compacta, putamen, frontal cortex area 8 and angular gyrus area 39, in a total of 43 controls and 56 cases with PD-related pathology covering stages 1-6 of Braak. Up-regulation of IL-6ST was the only change in the substantia nigra at stages 1-2. Down-regulation of the majority of members examined occurred in the substantia nigra from stage 4 onwards. However, region-dependent down- and up-regulation of selected mRNAs occurred in the putamen and frontal cortex, whereas only mRNA up-regulated mRNAs were identified in the angular cortex from stage 3 onwards in PD cases. Protein studies in frontal cortex revealed increased IL6 expression and reduced IL-10 with ELISA, and increased IL-6 with western blotting in PD. Immunohistochemistry revealed localization of IL-5, IL-6 and IL-17 receptors in glial cells, mainly microglia; IL-5, IL-10 and M-CSF in neurons; TNF-α in neurons and microglia; and active NF-κB in the nucleus of subpopulations of neurons and glial cells in PD. Distinct inflammatory responses, involving pro- and anti-inflammatory cytokines, and variegated mediators of the immune response occur in different brain regions at the same time in particular individuals. Available information shows that altered α-synuclein solubility and aggregation, Lewy body formation, oxidative damage and neuroinflammation converge in the pathogenesis of PD.