|Title||Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Drouin-Ouellet, Janelle, Isabelle St-Amour, Martine Saint-Pierre, Jérôme Lamontagne-Proulx, Jasna Kriz, Roger A. Barker, and Francesca Cicchetti|
|Journal||Int J Neuropsychopharmacol|
|Date Published||2014 Dec 07|
|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|
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.
|Alternate Journal||Int. J. Neuropsychopharmacol.|
|PubMed Central ID||PMC4438545|
|Grant List||/ / Canadian Institutes of Health Research / Canada|