Microglia Ablation and Downstream Effects in the Cerebrospinal Fluid Proteome

Disease-related activation of glial cells leads to changes in the cerebrospinal fluid (CSF) proteome. However, assigning such protein changes to their cellular origins is often difficult. Here, we used microglia (and macrophage) depletion in mice to identify CSF proteins of microglial origin. Young mice were treated with an inhibitor of the colony-stimulating factor 1 receptor, resulting in an almost complete ablation of microglial cells (and brain macrophages). Depleting microglia revealed profound changes in the CSF proteome. Nineteen proteins showed an overall reduction of at least 90%, suggesting a direct microglial or macrophage origin. Strikingly, we also observed an increase in many neuronal and synaptic proteins, likely reflecting compensatory neural changes including the accumulation of certain neuronal proteins that normally act as ligands for receptors on microglia cells, such as fractalkine or interleukin-34. In contrast to the robust changes in microglial and neuronal proteins, there was no evidence of astrogliosis after microglia ablation as determined by proteome analysis and brain histology. These observations are crucial for interpreting changes to the CSF proteome in relation to neuroinflammatory changes in neurological diseases.