Antibody-mediated phagocytosis of the amyloid β-peptide in microglia is differentially modulated by C1q

Microglial ingestion of the amyloid beta -peptide (A beta) has been viewed as a therapeutic target in Alzheimer's disease, in that approaches that enhance clearance of A beta relative to its production are predicted to result in decreased senile plaque formation, a proposed contributor to neuropathology. In vitro, scavenger receptors mediate ingestion of fibrillar A beta (fA beta) by microglia. However, the finding that cerebral amyloid deposition in a transgenic mouse model of Alzheimer's disease was diminished by inoculation with synthetic A beta has suggested a possible therapeutic role for anti-A beta Ab-mediated phagocytosis. Microglia also express C1qR(P),, a receptor for complement protein Clq, ligation of which in vitro enhances phagocytosis of immune complexes formed with IgG levels below that required for optimal FcR-mediated phagocytosis. The data presented here demonstrate FcR-dependent ingestion of A beta -anti-A beta complexes (IgG-fA beta) by microglia that is a function of the amount of Ab used to form immune complexes. In addition, Clq incorporated into IgG-fA beta enhanced microglial uptake of these complexes when they contained suboptimal levels of anti-A beta Ab. Mannose binding lectin and lung surfactant protein A, other ligands of C1qR(P). also enhanced ingestion of suboptimally opsonized IgG-fA beta, whereas control proteins did not. Our data suggest that C1qR(P)-mediated events may promote efficient ingestion of A beta at low Ab titers, and this may be beneficial in paradigms that seek to clear amyloid via FcR-mediated mechanisms by minimizing the potential for destructive Ab-induced complement-mediated processes.