title: CD47 does not mediate amyloid-β(1-42) protofibril-stimulated microglial cytokine release.
abstract: Neuroinflammation triggered by accumulation of amyloid-β protein (Aβ) is a significant component of the Alzheimer's disease (AD) brain. Senile plaques composed of Aβ attract and activate microglia cells resulting in cytokine secretion and a proinflammatory environment. The mechanism by which Aβ activates microglia is complex and involves numerous cellular components. One receptor potentially involved in Aβ recognition and the ensuing microglia proinflammatory response is CD47. Since there is significant interest in soluble aggregated Aβ species, we sought to determine if CD47 plays a key role in microglia cytokine release stimulated by soluble Aβ(1-42) protofibrils. Pretreatment of primary murine microglia with the CD47 antagonist peptide 4N1K significantly and potently inhibited both tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) secretion stimulated by Aβ(1-42) protofibrils. 4N1K displayed toxicity to the microglia but only at concentrations much higher than the observed inhibition. Surprisingly, 4N1K also potently inhibited TNFα secretion triggered by lipopolysaccharide which is not known to signal through CD47. Treatment of the microglia with a neutralizing anti-CD47 antibody failed to block the Aβ protofibril response even though comparable samples were completely inhibited by 4N1K. Finally, Aβ(1-42) protofibrils stimulated similar levels of secreted TNFα production in both wild-type and CD47(-/-) microglia and 4N1K still potently inhibited the Aβ protofibril response even in the CD47(-/-) microglia. The overall findings demonstrated that the microglial proinflammatory response to Aβ(1-42) protofibril is not dependent on CD47 and that 4N1K exhibits CD47-independent inhibitory activity.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri-St. Louis, United States.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Karki
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri-St. Louis, United States. Electronic address: nicholsmic@umsl.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Nichols
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C120273:4N1K peptide; D000682:Amyloid; D016229:Amyloid beta-Peptides; D057134:Antibodies, Neutralizing; D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D053583:Interleukin-1beta; D009842:Oligopeptides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42)
keywords: Aggregation; Amyloid-beta protein; CD47; Cytokines; Microglia; Protofibrils