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.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.

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…Furthermore, attenuation of microglia activation prevented alpha-synuclein-induced neurodegeneration (Cao et al, 2010). Microglial activation due to overexpression of alpha-synuclein has also been observed in PD patients (Drouin-Ouellet et al, 2014). As mentioned earlier, intranigral injection of LPS resulted in early microglia activation followed by a significant decrease in dopamine in the substantia nigra and striatum and dopaminergic cell loss (Castano et al, 1998).…”

“…Aberrant overexpression of proteins such as alpha-synuclein and neuromelanin has been implicated to trigger PD-related microglial activation (Cao et al, 2010;Drouin-Ouellet et al, 2014;Viceconte et al, 2015). Exposure to various PD-potentiating chemicals such as MPTP and manganese in cells has also led to microglial activation (Bae et al, 2006;Borrajo et al, 2014).…”

Mutant huntingtin protein expression and blood–spinal cord barrier dysfunction in huntington disease

“…23 We herein report, for the first time: (1) the presence and Quantifications were performed for the density of blood vessels per surface area of tissue, the Feret diameter of all blood vessels, and the percentage of blood vessels of a given diameter ( > or < 10 mm). 23 We herein report, for the first time: (1) the presence and Quantifications were performed for the density of blood vessels per surface area of tissue, the Feret diameter of all blood vessels, and the percentage of blood vessels of a given diameter ( > or < 10 mm).…”

“…Cervical gray or white matter and lumbar gray or white matter frozen sample dissections (approximately 15mg) from HD patients and age-matched healthy controls (see Table) were processed for Western blotting according to previously published protocols. 23 SDS electrophoresis gels were loaded with 20 mg of total protein per sample per well and separated for 1 hour and 30 minutes after applying 120V current. The resolved proteins were electrophoretically transferred onto a polyvinylidene difluoride membrane (VWR, Mississauga, Ontario, Canada) membrane (0.45 mm) overnight at 48C under a 20V current.…”

Malathion Neurotoxic Effects on Dopaminergic System in Mice: Role of Inflammation

“…Malathion was administered orally by gastric gavage every day for 8 weeks. The other two groups received two different anti-inflammatory drugs (purchased from Amriya Company for pharmaceutical industries) in conjunction with malathion for 8 weeks as follows: Group 3 (G3): "malathion+dexamethasone" M+DX-treated group: mice were given malathion plus subcutaneous dexamethasone injection "3 mg/kg/day" [16] and G4: "malathion+acetyl-salicylic acid" M+ASA-treated group: mice were given malathion plus intraperitoneal injection of ASA "100 mg/kg/day" [17]. Weights of the animals were recorded once a week throughout the experiment.…”