title: Antibody-mediated phagocytosis of the amyloid beta-peptide in microglia is differentially modulated by C1q.
abstract: Microglial ingestion of the amyloid beta-peptide (Abeta) has been viewed as a therapeutic target in Alzheimer's disease, in that approaches that enhance clearance of Abeta 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 Abeta (fAbeta) by microglia. However, the finding that cerebral amyloid deposition in a transgenic mouse model of Alzheimer's disease was diminished by inoculation with synthetic Abeta has suggested a possible therapeutic role for anti-Abeta 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 Abeta-anti-Abeta complexes (IgG-fAbeta) by microglia that is a function of the amount of Ab used to form immune complexes. In addition, C1q incorporated into IgG-fAbeta enhanced microglial uptake of these complexes when they contained suboptimal levels of anti-Abeta Ab. Mannose binding lectin and lung surfactant protein A, other ligands of C1qR(P), also enhanced ingestion of suboptimally opsonized IgG-fAbeta, whereas control proteins did not. Our data suggest that C1qR(P)-mediated events may promote efficient ingestion of Abeta 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.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Webster
authors.forename: M D
authors.initials: MD
authors.lastname: Galvan
authors.forename: E
authors.initials: E
authors.lastname: Ferran
authors.forename: W
authors.initials: W
authors.lastname: Garzon-Rodriguez
authors.forename: C G
authors.initials: CG
authors.lastname: Glabe
authors.forename: A J
authors.initials: AJ
authors.lastname: Tenner
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000502:physiology*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D002352:Carrier Proteins; D002460:Cell Line; D002478:Cells, Cultured; D002498:Centrifugation; D003094:Collagen / Q000378:metabolism / Q000502:physiology; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005293:Ferritins / Q000378:metabolism / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D017628:Microglia / Q000276:immunology* / Q000378:metabolism*; D024101:Mitochondrial Proteins; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D011069:Poly I / Q000378:metabolism / Q000494:pharmacology; D011134:Polysaccharides / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011951:Receptors, Complement / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D012709:Serum Albumin / Q000378:metabolism / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D000936:Antigen-Antibody Complex; C087299:C1QBP protein, human; C490193:C1qbp protein, mouse; C490195:C1qbp protein, rat; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D011134:Polysaccharides; D011951:Receptors, Complement; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D012709:Serum Albumin; C075222:amyloid beta-protein (1-42); C032402:complement 1q receptor; D011069:Poly I; D015922:Complement C1q; D003094:Collagen; D005293:Ferritins; C007789:fucoidan