1. Academic Validation
  2. Microglial inhibition alleviates alpha-synuclein propagation and neurodegeneration in Parkinson's disease mouse model

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

  • NPJ Parkinsons Dis. 2024 Feb 2;10(1):32. doi: 10.1038/s41531-024-00640-2.
Thuy Thi Lai 1 2 3 Young Eun Kim 4 5 Linh Thi Nhat Nguyen 1 Tinh Thi Nguyen 1 In Hee Kwak 1 6 Franziska Richter 2 3 Yun Joong Kim 7 Hyeo-Il Ma 1 6
Affiliations

Affiliations

  • 1 Hallym Neurological Institute, Hallym University, Anyang, Gyeonggi, 14068, South Korea.
  • 2 Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, 30559, Hannover, Germany.
  • 3 Center for Systems Neuroscience Hannover, Hannover, Germany.
  • 4 Hallym Neurological Institute, Hallym University, Anyang, Gyeonggi, 14068, South Korea. yekneurology@hallym.or.kr.
  • 5 Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University, Anyang, Gyeonggi, 14068, South Korea. yekneurology@hallym.or.kr.
  • 6 Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University, Anyang, Gyeonggi, 14068, South Korea.
  • 7 Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi, South Korea.
Abstract

The accumulation of alpha-synuclein (αSyn) 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 αSyn and neurodegeneration, while the inhibition of microglial activity may mitigate these effects. To test this hypothesis, αSyn preformed fibrils (PFF)-injected PD mouse model was employed. Co-injection of lipopolysaccharide (LPS) and PFF was performed to investigate if microglial reactivity intensified αSyn 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 αSyn pathology. Intrastriatal co-injection of LPS and PFF resulted in increased microglial reactivity, αSyn accumulation, and neurodegeneration compared to PFF injection alone. However, treatment with PLX5622 significantly suppressed microglial reactivity, reduced αSyn 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 αSyn pathology and neurodegeneration in PD. Furthermore, the results suggest that microglial inhibition may hold promise as a therapeutic strategy to delay the progression of αSyn pathology in PD.

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