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

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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.

Detaljer

Författare
  • Janelle Drouin-Ouellet
  • Isabelle St-Amour
  • Martine Saint-Pierre
  • Jérôme Lamontagne-Proulx
  • Jasna Kriz
  • Roger A Barker
  • Francesca Cicchetti
Enheter & grupper
Externa organisationer
  • University of Cambridge
Forskningsområden

Nyckelord

Originalspråkengelska
TidskriftInternational Journal of Neuropsychopharmacology
Volym18
Utgåva nummer6
StatusPublished - 2015
PublikationskategoriForskning
Peer review utfördJa