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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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organization
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
  • pmid:25522431
  • 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
2024-04-19 14:00:19
@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}},
  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}},
  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}},
  doi          = {{10.1093/ijnp/pyu103}},
  volume       = {{18}},
  year         = {{2015}},
}