Soluble CSF1R promotes microglial activation and amyloid clearance in alzheimer's disease

The colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase essential for microglial development and homeostasis. While dysregulated CSF1R signaling has been implicated in Alzheimer's disease (AD), the biological function of its soluble ectodomain (sCSF1R)-generated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated cleavage-remains poorly understood in neurodegeneration.

We quantified sCSF1R levels in the brain and cerebrospinal fluid (CSF) of 5×FAD transgenic mice and wild-type controls using ELISA and immunoblotting, and reanalyzed publicly available CSF proteomic datasets from three independent, clinically characterized AD cohorts. Functional studies were performed in primary microglial cultures and through hippocampal delivery of recombinant sCSF1R into 5×FAD mice to evaluate its effects on microglial activity and amyloid pathology.

In this study, we identify sCSF1R as a previously unrecognized, functionally active modulator of microglial responses in AD. Analysis of three independent clinical cohorts revealed significantly elevated sCSF1R levels in the CSF of AD patients, a finding recapitulated in both the brain and CSF of 5×FAD transgenic mice. Importantly, sCSF1R concentrations showed positive correlations with core AD biomarkers-including total tau, phosphorylated tau, and β-amyloid 1-42 (Aβ42)-and with measures of cognitive performance, highlighting its clinical significance and suggesting that sCSF1R may serve as a marker of disease-associated microglial responses. Functionally, recombinant sCSF1R enhanced microglial survival, migration, proinflammatory signaling, and Aβ phagocytosis in vitro. In vivo, administration of sCSF1R promoted microglial clustering around amyloid plaques, reduced Aβ deposition, and attenuated plaque-associated neuritic dystrophy in 5×FAD mice. Finally, we found that soluble TREM2 (sTREM2)-a CSF biomarker and potent activator of microglia-stimulates ADAM17-dependent cleavage of membrane-bound CSF1R, thereby driving the generation of sCSF1R. Collectively, these findings establish sCSF1R as a novel regulator of microglial function in AD and reveal a regulatory axis linking sTREM2, ADAM17 activity, and CSF1R shedding with potential implications for disease modulation.

These findings identify sCSF1R as a novel component of the neuroimmune signaling network in AD and highlight its dual potential as a CSF biomarker of beneficial microglial activation and a candidate therapeutic modulator of neuroinflammation and amyloid pathology.