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

Drouin-Ouellet, Janelle LU ; St-Amour, Isabelle; Saint-Pierre, Martine; Lamontagne-Proulx, Jérôme; Kriz, Jasna; Barker, Roger A LU and Cicchetti, Francesca (2015) In International Journal of Neuropsychopharmacology 18(6).
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... (More)

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.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Aged, Aged, 80 and over, 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, alpha-Synuclein, Journal Article, Research Support, Non-U.S. Gov't
in
International Journal of Neuropsychopharmacology
volume
18
issue
6
publisher
Cambridge University Press
external identifiers
  • scopus:84939213691
ISSN
1469-5111
DOI
10.1093/ijnp/pyu103
language
English
LU publication?
no
id
06c3d270-f9f0-4d47-95ff-803297744d69
date added to LUP
2016-11-22 09:01:21
date last changed
2017-09-10 05:11:57
@article{06c3d270-f9f0-4d47-95ff-803297744d69,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Drouin-Ouellet, Janelle and St-Amour, Isabelle and Saint-Pierre, Martine and Lamontagne-Proulx, Jérôme and Kriz, Jasna and Barker, Roger A and Cicchetti, Francesca},
  issn         = {1469-5111},
  keyword      = {Aged,Aged, 80 and over,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,alpha-Synuclein,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {6},
  publisher    = {Cambridge University Press},
  series       = {International Journal of Neuropsychopharmacology},
  title        = {Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease},
  url          = {http://dx.doi.org/10.1093/ijnp/pyu103},
  volume       = {18},
  year         = {2015},
}