title: Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia.
abstract: Complement components and their receptors are found within and around amyloid β (Aβ) cerebral plaques in Alzheimer's disease (AD). Microglia defend against pathogens through phagocytosis via complement component C3 and/or engagement of C3 cleavage product iC3b with complement receptor type 3 (CR3, Mac-1). Here, we provide direct evidence that C3 and Mac-1 mediate, in part, phagocytosis and clearance of fibrillar amyloid-β (fAβ) by murine microglia in vitro and in vivo. Microglia took up not only synthetic fAβ(42)  but also amyloid cores from patients with AD, transporting them to lysosomes in vitro. Fibrillar Aβ(42)  uptake was significantly attenuated by the deficiency or knockdown of C3 or Mac-1 and scavenger receptor class A ligands. In addition, C3 or Mac-1 knockdown combined with a scavenger receptor ligand, fucoidan, further attenuated fibrillar Aβ(42)  uptake by N9 microglia. Fluorescent fibrillar Aβ(42)  microinjected cortically was significantly higher in C3 and Mac-1 knockout mice compared with wild-type mice 5 days after surgery, indicating reduced clearance in vivo. Together, these results demonstrate that C3 and Mac-1 are involved in phagocytosis and clearance of fAβ by microglia, providing support for a potential beneficial role for microglia and the complement system in AD pathogenesis. © 2012 Wiley Periodicals, Inc.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Frost
authors.forename: Soyon
authors.initials: S
authors.lastname: Hong
authors.forename: Ming
authors.initials: M
authors.lastname: Jin
authors.forename: Beth
authors.initials: B
authors.lastname: Ostaszewski
authors.forename: Ganesh M
authors.initials: GM
authors.lastname: Shankar
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Costantino
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002461:Cell Line, Transformed; D015932:Complement C3c / Q000172:deficiency / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008024:Ligands; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008845:Microinjections; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D015932:Complement C3c; D016207:Cytokines; D008024:Ligands; D051907:Lysosomal Membrane Proteins; D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C075222:amyloid beta-protein (1-42)