Objective: To evaluate whether microglial activation aggravates synucleinopathy progression in Parkinson’s disease (PD) mouse model.

Background: Alpha-synuclein (αSyn) accumulation underlay the main pathological process of Parkinson’s disease (PD). In addition, inflammation is known for one of the mechanisms involved in PD pathogenesis. Hence, we hypothesize that microglial activation aggravates αSyn propagation and the following neurodegeneration. In addition, we evaluated whether reducing inflammatory response salvage this or not.

Method: For this study, we used αSyn preformed fibrils (PFF)-injected PD mouse model. To know whether additive inflammatory activation (focused on microglia) aggravates αSyn propagation, lipopolysaccharide (LPS, 10 µg) was co-injected with PFF into the striatum of mice, and it was compared with control vehicle and PFF.  In another set of experiments, oral PLX5622 (65mg/kg) – an inhibitor of colony-stimulating factor 1 receptor, microglial inhibitor – was treated for 2 weeks each before and after PFF injection, and this group was compared with mice using control substance and PFF. The severity of inflammation, αSyn propagation, and neurodegeneration was evaluated by immunostaining or western blot.

Results: In the present study, intrastriatal co-injection of LPS and PFF resulted in the greater αSyn accumulation and propagation in the brain, which was followed by greater neurodegeneration. And PLX5622 treatment significantly suppresses microglial activation and reduces the progression of αSyn pathology following PFF injection in the brain. Moreover, microglial inhibition by PLX5622 alleviates the degeneration of dopaminergic neurons in the PFF-injected PD mouse model.

Conclusion: Collectively, these data suggest that inflammation, especially microglial activation facilitates αSyn propagation and neurodegeneration. And it implies that microglial deactivation can be a good treatment target for delaying αSyn pathological progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/microglial-activation-facilitates-alpha-synuclein-propagation-and-neurodegeneration-in-%ce%b1syn-preformed-fibrils-pff-injected-pd-mouse-model/