title: Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines.
abstract: Microglia undergo a phenotypic activation in response to fibrillar beta-amyloid (fAbeta) deposition in the brains of Alzheimer's disease (AD) patients, resulting in their elaboration of inflammatory molecules. Despite the presence of abundant plaque-associated microglia in the brains of AD patients and in animal models of the disease, microglia fail to efficiently clear fAbeta deposits. However, they can be induced to do so during Abeta vaccination therapy attributable to anti-Abeta antibody stimulation of IgG receptor (FcR)-mediated phagocytic clearance of Abeta plaques. We report that proinflammatory cytokines attenuate microglial phagocytosis stimulated by fAbeta or complement receptor 3 and argue that this may, in part, underlie the accumulation of fAbeta-containing plaques within the AD brain. The proinflammatory suppression of fAbeta-elicited phagocytosis is dependent on nuclear factor kappaB activation. Significantly, the proinflammatory cytokines do not inhibit phagocytosis elicited by antibody-mediated activation of FcR, which may contribute to the efficiency of Abeta vaccination-based therapy. Importantly, the proinflammatory suppression of fAbeta phagocytosis can be relieved by the coincubation with anti-inflammatory cytokines, cyclooxygenase inhibitors, ibuprofen, or an E prostanoid receptor antagonist, suggesting that proinflammatory cytokines induce the production of prostaglandins, leading to an E prostanoid receptor-dependent inhibition of phagocytosis. These findings support anti-inflammatory therapies for the treatment of AD.
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koenigsknecht-Talboo
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000494:pharmacology; D004558:Electric Stimulation; D007074:Immunoglobulin G / Q000494:pharmacology*; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D007074:Immunoglobulin G; D007375:Interleukin-1; D007378:Interleukins; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35)