Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease.

Publication Type:

Journal Article

Authors:

Drouin-Ouellet, Janelle; Isabelle St-Amour; Saint-Pierre, Martine; Lamontagne-Proulx, Jérôme; Jasna Kriz; Barker, Roger A; Cicchetti, Francesca

Source:

Int J Neuropsychopharmacol, Volume 18, Issue 6 (2014)

Keywords:

Aged, Aged, 80 and over, alpha-Synuclein, Animals, Antiparkinson Agents, B-Lymphocytes, Brain, Case-Control Studies, Dexamethasone, Disease Models, Animal, Female, Green Fluorescent Proteins, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Middle Aged, Monocytes, Parkinson Disease, Time Factors, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptors, Up-Regulation

Abstract:

BACKGROUND: Accumulating evidence supports a role for the immune system in the pathogenesis of Parkinson's disease. Importantly, recent preclinical studies are now suggesting a specific contribution of inflammation to the α-synuclein-induced pathology seen in this condition.METHODS: We used flow cytometry and western blots to detect toll-like receptor 2 and 4 expression in blood and brain samples of Parkinson's disease patients and mice overexpressing human α-synuclein. To further assess the effects of α-synuclein overexpression on the innate immune system, we performed a longitudinal study using Thy1.2-α-synuclein mice that expressed a bicistronic DNA construct (reporter genes luciferase and green fluorescent protein) under the transcriptional control of the murine toll-like receptor 2 promoter.RESULTS: Here, we report increases in toll-like receptors 2 and 4 expression in circulating monocytes and of toll-like receptor 4 in B cells and in the caudate/putamen of Parkinson's disease patients. Monthly bioluminescence imaging of Thy1.2-α-synuclein mice showed increasing toll-like receptor 2 expression from 10 months of age, although no change in toll-like receptor 2 and 4 expression was observed in the blood and brain of these mice at 12 months of age. Dexamethasone treatment starting at 5 months of age for 1 month significantly decreased the microglial response in the brain of these mice and promoted functional recovery as observed using a wheel-running activity test.CONCLUSION: Our results show that toll-like receptors 2 and 4 are modulated in the blood and brain of Parkinson's disease patients and that overexpression of α-synuclein leads to a progressive microglial response, the inhibition of which has a beneficial impact on some motor phenotypes of an animal model of α-synucleinopathy.