Accelerated phagocytosis of amyloid-β by mouse and human microglia overexpressing the macrophage colony-stimulating factor receptor

Microglia surrounding Abeta plaques in Alzheimer's disease and in the APPV717F transgenic mouse model of Alzheimer's disease have enhanced immunoreactivity for the macrophage colony-stimulating factor receptor (M-CSFR), encoded by the proto-oncogene c-fins. Increased expression of M-CSFR on cultured microglia results in proliferation and release of pro-inflammatory cytokines and expression of inducible nitric-oxide synthase. We transfected mouse BV-2 and human SV-A3 microglia to overexpress M-CSFR and examined microglial phagocytosis of fluorescein-conjugated Abeta. Flow cytometry and laser confocal microscopy showed accelerated phagocytosis of Abeta in mouse and human microglia because of M-CSFR overexpression that was time-and concentration-dependent. In contrast, microglial uptake of 1-mum diameter polystyrene microspheres was not enhanced by M-CSFR overexpression. Microglial uptake of Abeta was blocked by cytochalasin D, which inhibits phagocytosis. M-CSFR overexpression increased the mRNA for macrophage scavenger receptor A, and fucoidan blocking of macrophage scavenger receptors inhibited uptake of Abeta. M-CSFR antibody blocking experiments demonstrated that increased Abeta uptake depended on the interaction of the M-CSFR with its ligand. These results suggest that overexpression of M-CSFR in APPV717F mice may prime microglia for phagocytosis of Abeta after immunization.