Targeting brain colony stimulating factor 1 receptor for phagocytic microglia reprogramming as a potential strategy against brain inflammation

Colony stimulating factor 1 receptor (CSF1R) is the master regulator of microglial development, homeostasis, and survival in the central nervous system. Dysfunction of the CSF1R pathway has been implicated in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Microglial phenotype critically depends on the predominant metabolic pathway: homeostatic microglia rely on oxidative phosphorylation (OXPHOS), whereas inflammatory activation triggers a metabolic switch toward aerobic glycolysis, supporting rapid ATP production and synthesis of pro-inflammatory mediators. Preclinical studies show that pharmacological CSF1R inhibition, using compounds such as PLX3397, GW2580, and JNJ-40346527, reprograms microglia toward a pro-phagocytic, anti-inflammatory phenotype, improving amyloid clearance, reducing neuroinflammation, and restoring synaptic plasticity, without necessarily compromising microglial survival or proliferation. The interaction between CSF1R and TREM2 further regulates microglial phenotypic transitions. Despite encouraging results in animal models and ongoing clinical trials, limitations remain due to systemic side effects associated with chronic CSF1R inhibition. Identifying more selective biomarkers (e.g., TREM2, TSPO) and metabolic targets will be essential for developing disease-modifying therapies against neuroinflammation in AD, Parkinson's disease, and other neurodegenerative conditions.