Significantly elevated levels of soluble CSF1R () were found in the cerebrospinal fluid of Alzheimer's disease patients compared to controls.
sCSF1R levels were positively correlated with key Alzheimer's biomarkers such as total tau, phosphorylated tau, and β-amyloid 1-42.
Increased sCSF1R concentrations were associated with better cognitive performance in Alzheimer's patients.
Recombinant sCSF1R enhanced microglial survival, migration, proinflammatory signaling, and the ability to engulf amyloid in laboratory studies.
In 5×FAD mice, administration of sCSF1R led to microglial clustering around amyloid plaques and reduced amyloid deposition.
Soluble TREM2 was found to stimulate the cleavage of membrane-bound CSF1R, which increases the production of sCSF1R.
Simplified
BACKGROUND: 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 ()-generated by a disintegrin and metalloproteinase 17 ()-mediated cleavage-remains poorly understood in neurodegeneration.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Key numbers
1,170 of 1,170 individuals
Level Increase
Individuals with elevated levels in from the Knight Alzheimer Disease Research Center cohort.
1 of 1
Correlation with Cognitive Performance
levels positively correlate with cognitive performance measured by .
5 µg
In Vivo Microglial Activation
Amount of protein injected into the hippocampus of 5×FAD mice.
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Declarations. Ethics approval and consent to participate : All animal experiments were approved by the Animal Ethics Committee of the Xiamen University and were conducted in compliance with all relevant ethical regulations for animal testing and research. Consent for publication: Not Applicable. Competing interests: G.B. consults for SciNeuro Pharmaceuticals. All other authors declare no competing interests.
