Microglial inhibition alleviates alpha-synuclein propagation and neurodegeneration in Parkinson's disease mouse model

The accumulation of alpha-synuclein (alpha Syn) is widely recognized as the main pathological process in Parkinson's disease (PD). Additionally, neuroinflammation is considered to be one of the contributing mechanisms in the development of PD. In light of this, it is hypothesized that the reactive microglia exacerbate the propagation of alpha Syn and neurodegeneration, while the inhibition of microglial activity may mitigate these effects. To test this hypothesis, alpha Syn preformed fibrils (PFF)-injected PD mouse model was employed. Co-injection of lipopolysaccharide (LPS) and PFF was performed to investigate if microglial reactivity intensified alpha Syn propagation and neurodegeneration. Additionally, oral administration of PLX5622, a microglial inhibitor that targets the colony-stimulating factor 1 receptor, was given for two weeks before and after PFF injection each to explore if microglial inhibition could prevent or reduce alpha Syn pathology. Intrastriatal co-injection of LPS and PFF resulted in increased microglial reactivity, alpha Syn accumulation, and neurodegeneration compared to PFF injection alone. However, treatment with PLX5622 significantly suppressed microglial reactivity, reduced alpha Syn pathology, and alleviated dopaminergic neuron degeneration in the PD mouse model injected with PFF. Based on these findings, it is evident that microglial reactivity plays a crucial role in the progression of alpha Syn pathology and neurodegeneration in PD. Furthermore, the results suggest that microglial inhibition may hold promise as a therapeutic strategy to delay the progression of alpha Syn pathology in PD.