title: 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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Janelle
authors.initials: J
authors.lastname: Drouin-Ouellet
authors.affiliation: 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).
authors.forename: Isabelle
authors.initials: I
authors.lastname: St-Amour
authors.affiliation: 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).
authors.forename: Martine
authors.initials: M
authors.lastname: Saint-Pierre
authors.affiliation: 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).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lamontagne-Proulx
authors.affiliation: 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).
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.affiliation: 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).
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cicchetti
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C497604:SNCA protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D003907:Dexamethasone
keywords: TLR2; TLR4; bioluminescence imaging; dexamethasone; microglia; α-synuclein