LONG-TERM CSF1R INHIBITION MODULATES TREM2-DEPENDENT MICROGLIAL SIGNALING AND AMELIORATES ALZHEIMER’S DISEASE PATHOLOGY

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) plaque deposition, neurofibrillary tau tangles, and chronic neuroinflammation driven by sustained microglial activation. While microglia initially exert protective functions through protein clearance, prolonged activation ultimately accelerates synaptic dysfunction and neurodegeneration. Colony-stimulating factor 1 receptor (CSF1R), predominantly expressed in microglia, is essential for their survival, proliferation, and disease-associated activation, making it an attractive therapeutic target for modulating maladaptive neuroinflammation in AD. Here, we evaluated the therapeutic efficacy and mechanism of action of a novel CSF1R inhibitor using a clinically relevant long-term treatment paradigm. The CSF1R inhibitor was administered via chow to 5xFAD mice for three months, followed by behavioral testing and comprehensive molecular analyses, including immunohistochemistry, transcriptomic profiling and protein assays. Based on prior single-cell RNA-sequencing data implicating suppression of TREM2-associated pathways by CSF1R inhibition, we further investigated potential CSF1R- TREM2 signaling interactions in vitro using Aβ-stimulated BV2 microglial cells. Chronic CSF1R inhibition resulted in modest but significant improvements in cognitive performance in 5xFAD mice, accompanied by a marked attenuation of neuroinflammatory markers. Mechanistically, CSF1R inhibition led to a dose-dependent downregulation of TREM2, TYROBP, and SYK signaling, indicating suppression of disease-associated microglial activity states. Together, these findings support a functional crosstalk between CSF1R and TREM2 pathways in regulating microglial response during AD progression. Our study highlights long-term CSF1R inhibition as a promising strategy to recalibrate microglial activity and mitigate neurodegeneration in AD.