title: Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro.
abstract: C-reactive protein (CRP) and serum amyloid P component (SAP), two major classical pentraxins in humans, are soluble pattern recognition molecules that regulate the innate immune system, but their chaperone activities remain poorly understood. Here, we examined their effects on the amyloid fibril formation from Alzheimer's amyloid β (Aβ) (1-40) and on that from D76N β2-microglobulin (β2-m) which is related to hereditary systemic amyloidosis. CRP and SAP dose-dependently and substoichiometrically inhibited both Aβ(1-40) and D76N β2-m fibril formation in a Ca(2+)-independent manner. CRP and SAP interacted with fresh and aggregated Aβ(1-40) and D76N β2-m on the fibril-forming pathway. Interestingly, in the presence of Ca(2+), SAP first inhibited, then significantly accelerated D76N β2-m fibril formation. Electron microscopically, the surface of the D76N β2-m fibril was coated with pentameric SAP. These data suggest that SAP first exhibits anti-amyloidogenic activity possibly via A face, followed by pro-amyloidogenic activity via B face, proposing a model that the pro- and anti-amyloidogenic activities of SAP are not mutually exclusive, but reflect two sides of the same coin, i.e., the B and A faces, respectively. Finally, SAP inhibits the heat-induced amorphous aggregation of human glutathione S-transferase. A possible role of pentraxins to maintain extracellular proteostasis is discussed.
authors.affiliation: Life Science Unit, Tenure-Track Program for Innovative Research, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Ozawa
authors.affiliation: Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nomura
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK.
authors.forename: P Patrizia
authors.initials: PP
authors.lastname: Mangione
authors.affiliation: Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Okoshi
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.affiliation: Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Naiki
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics / Q000473:pathology; D000682:Amyloid / Q000097:blood; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000235:genetics; D000686:Amyloidosis / Q000097:blood* / Q000235:genetics / Q000473:pathology; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D005982:Glutathione Transferase / Q000097:blood / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D020125:Mutation, Missense; D066263:Protein Aggregation, Pathological / Q000097:blood / Q000235:genetics; D017510:Protein Folding; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000097:blood / Q000235:genetics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000683:Serum Amyloid P-Component; D001613:beta 2-Microglobulin; D002097:C-Reactive Protein; D005982:Glutathione Transferase; D002118:Calcium