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Int J Neuropsychopharmacol. 2014 Dec 7;18(6). pii: pyu103. doi: 10.1093/ijnp/pyu103.

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

Author information

1
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom (Drs Drouin-Ouellet and Barker); Centre de recherche du CHU de Québec, Québec, QC, Canada (Dr St-Amour, Ms Saint-Pierre, Mr Lamontagne-Proulx, and Dr Cicchetti); Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Québec, QC, Canada (Dr Kriz); and Département de psychiatrie et neurosciences, Université Laval, Québec, QC, Canada (Drs Kriz and Cicchetti). jd628@cam.ac.uk francesca.cicchetti@crchudequebec.ulaval.ca.
2
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom (Drs Drouin-Ouellet and Barker); Centre de recherche du CHU de Québec, Québec, QC, Canada (Dr St-Amour, Ms Saint-Pierre, Mr Lamontagne-Proulx, and Dr Cicchetti); Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Québec, QC, Canada (Dr Kriz); and Département de psychiatrie et neurosciences, Université Laval, Québec, QC, Canada (Drs Kriz and Cicchetti).

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.

KEYWORDS:

TLR2; TLR4; bioluminescence imaging; dexamethasone; microglia; α-synuclein

PMID:
25522431
PMCID:
PMC4438545
DOI:
10.1093/ijnp/pyu103
[Indexed for MEDLINE]
Free PMC Article

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