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

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.

• Authors: Janelle Drouin-Ouellet, Isabelle St-Amour, Martine Saint-Pierre, Jérôme Lamontagne-Proulx, Jasna Kriz, Roger A Barker, Francesca Cicchetti
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 18 Issue 6 (Dec 07 2014) ISSN: 1469-5111 [Electronic] England
• PMID: 25522431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of CINP.

Chemical References

• Antiparkinson Agents
• SNCA protein, human
• TLR2 protein, human
• TLR4 protein, human
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Toll-Like Receptors
• alpha-Synuclein
• Green Fluorescent Proteins
• Dexamethasone

Topics

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