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Antibody-Mediated Phagocytosis of the Amyloid -Peptide in Microglia Is Differentially Modulated by C1q¹

Scott D. Webster^*, Manuel D. Galvan^*, Erick Ferran^*, William Garzon-Rodriguez, Charles G. Glabe^* and Andrea J. Tenner^2,*

^* Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; and Center for Pharmaceutical Biotechnology, University of Colorado Health Sciences Center, University of Colorado, Denver, CO 80262

Microglial ingestion of the amyloid -peptide (A) has been viewed as a therapeutic target in Alzheimer’s disease, in that approaches that enhance clearance of A 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 (fA) 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 has suggested a possible therapeutic role for anti-A Ab-mediated phagocytosis. Microglia also express C1qR_P, 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 A-anti-A complexes (IgG-fA) by microglia that is a function of the amount of Ab used to form immune complexes. In addition, C1q incorporated into IgG-fA enhanced microglial uptake of these complexes when they contained suboptimal levels of anti-A Ab. Mannose binding lectin and lung surfactant protein A, other ligands of C1qR_P, also enhanced ingestion of suboptimally opsonized IgG-fA, whereas control proteins did not. Our data suggest that C1qR_P-mediated events may promote efficient ingestion of A 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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