Objective: To investigate inflammatory change and Toll-like receptor (TLR) expression in human post-mortem Parkinson’s disease (PD) brains and to test the efficacy of TLR-blocking agents in a novel rodent PD model.

Background: Approximately 80% of PD patients have a poor outcome (postural instability, dementia, death) after 10 years from diagnosis. What determines the rate of disease progression is unknown, but neuroinflammation is a possible factor and a promising candidate for disease-modifying interventions. TLRs are a key component of this inflammatory response but their role in PD progression has not been fully explored.

Methods: Post-mortem brain tissue from 18 PD cases and 9 age-matched controls was used. Immunohistochemistry was performed in 8 regions for neuroinflammatory markers (Iba1, HLA-DR, TLR2/TLR4). TLR2/TLR4 expression was evaluated by Western blot and qPCR in 4 brain regions. In a novel rat PD model based on transvascular delivery of alpha-synuclein fibrils, changes in TLR2/TLR4 levels were determined by Western blot at 2,4 and 6 months. Subsequently, we compared the effects of 2 potential TLR-blockers (Candesartan cilexetil and TAK242). Rats were treated for 2 months with Candesartan, TAK242 or vehicle. TLR2/TLR4 expression was evaluated in monocytes using flow cytometry at baseline, 1 and 2 months. After 2 months, TLR-levels were measured in brain by Western blot.

Results: Activated microglia were increased in the hippocampus, amygdala and prefrontal cortex of human PD brains compared to controls (p=0.054, p=0.048, p=0.034, respectively). TLR2 but not TLR4 levels were increased in the hippocampus of PD compared to controls (p=0.003, p=0.192, respectively). In the rat model an increase in Iba1 and TLR4 levels in the brainstem was observed starting at 2 months, reaching significance at 6 months post-injection. After a 2-month treatment, TAK242 led to a decrease in both TLR2+ and TLR4+ monocytes while Candesartan did not. TLR levels in the brainstem were also decreased after TAK242 treatment, but not Candesartan. This suggests that TAK242 is a more effective TLR-blocking agent.

Conclusions: Neuroinflammation in human PD and our novel PD rodent model is associated with an increase in TLRs. Our pilot data indicates that TAK242 is an effective blocker of TLRs and we are now investigating its long-term impact on neurodegeneration in our rodent model, which may have implications for treating human PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-post-mortem-and-in-vivo-study-of-neuroinflammation-and-toll-like-receptors-in-parkinsons-disease/