Amyloidogenesis recapitulated in cell culture: a peptide inhibitor provides direct evidence for the role of heparan sulfate and suggests a new treatment strategy.
To date 22 different polypeptides, including Abeta in Alzheimer's disease and PrP(Sc) in prion disorders, are known to re-fold and assemble into highly organized fibrils, which associate with heparan sulfate (HS) proteoglycans to form tissue deposits called amyloid. Mononuclear phagocytes have long been thought to be involved in this process, and we describe a monocytic cell culture system that can transform the acute-phase protein serum amyloid A (SAA1.1) into AA-amyloid and appears to recapitulate all the main features of amyloidogenesis observed in vivo. These features in common include nucleation-dependent kinetics, identical proteolytic processing of SAA1.1, and co-deposition of HS with the fibrils. Heparin and polyvinylsulfonate previously reported to block AA-amyloidogenesis in mice are also effective inhibitors in this cell culture model. Furthermore, a synthetic peptide (27-mer) corresponding to a HS binding site of SAA, blocks amyloid deposition at a concentration that is several-orders-of-magnitude lower than any other peptide-based inhibitor previously reported. The 27-mer's inhibitory activity may target the amyloidogenic pathway specifically as it does not interfere with the binding of SAA to monocytes. These data provide direct evidence that SAA1.1:HS interactions are a critical step in AA-amyloidogenesis and suggest a novel treatment strategy for other amyloidoses.
Elimova
Elena
E
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Kisilevsky
Robert
R
Szarek
Walter A
WA
Ancsin
John B
JB
D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy / Q000209:etiology*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000502:physiology*; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011145:Polyvinyls / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000682:Amyloid; D006493:Heparin; D006497:Heparan Sulfate; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; D011145:Polyvinyls; D020033:Protein Isoforms; D000685:Serum Amyloid A Protein; C500435:SAA1.1 protein (77-103); C019050:polyvinyl sulfate