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

Int J Neuropsychopharmacol. 2014 Dec 7;18(6):pyu103. doi: 10.1093/ijnp/pyu103.


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.

Keywords: TLR2; TLR4; bioluminescence imaging; dexamethasone; microglia; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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