Antibody-Mediated Phagocytosis of the Amyloid β-Peptide in Microglia Is Differentially Modulated by C1q

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Abstract
Microglial ingestion of the amyloid β-peptide (Aβ) has been viewed as a therapeutic target in Alzheimer’s disease, in that approaches that enhance clearance of Aβ 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 Aβ (fAβ) by microglia. However, the finding that cerebral amyloid deposition in a transgenic mouse model of Alzheimer’s disease was diminished by inoculation with synthetic Aβ has suggested a possible therapeutic role for anti-Aβ Ab-mediated phagocytosis. Microglia also express C1qRP, a receptor for complement protein C1q, 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 Aβ-anti-Aβ complexes (IgG-fAβ) by microglia that is a function of the amount of Ab used to form immune complexes. In addition, C1q incorporated into IgG-fAβ enhanced microglial uptake of these complexes when they contained suboptimal levels of anti-Aβ Ab. Mannose binding lectin and lung surfactant protein A, other ligands of C1qRP, also enhanced ingestion of suboptimally opsonized IgG-fAβ, whereas control proteins did not. Our data suggest that C1qRP-mediated events may promote efficient ingestion of Aβ 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.

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