Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition

Area of Science:

• Neuroscience
• Immunology
• Neurodegenerative Diseases

Background:

• Parkinson's disease (PD) involves alpha-synuclein (α-syn) aggregates, neuroinflammation, and dopamine neuron loss.
• Microglia activation precedes neurodegeneration in PD models, suggesting a potential therapeutic target.
• The study investigates the role of colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion in PD pathology.

Purpose of the Study:

• To determine if CSF1R-mediated microglial depletion affects α-syn aggregation in the Parkinson's disease model.
• To assess the impact of microglial depletion on nigrostriatal degeneration.
• To evaluate the effect on microglial responses to α-syn pathology.

Main Methods:

• Rats received intrastriatal injections of α-syn preformed fibrils (PFFs) or saline.
• Continuous administration of a CSF1R inhibitor (Pexidartinib) depleted microglia for 2 or 6 months.
• Microglial markers (Iba-1, MHC-II), α-syn pathology (pSyn), and neuronal degeneration were analyzed.

Main Results:

• CSF1R inhibition significantly depleted microglia (approx. 43%) in the substantia nigra pars compacta (SNpc).
• Microglial depletion did not affect α-syn aggregation, nigral neuron degeneration, or microglial activation markers around inclusions.
• Long-term inhibition paradoxically increased the size and MHC-II expression of remaining microglia in extranigral regions.

Conclusions:

• CSF1R inhibition does not modify the microglial response to nigral α-syn inclusions in this PD model.
• Microglial depletion via CSF1R inhibition is not a viable disease-modifying strategy for Parkinson's disease.