The understanding of why and how proteins misfold and aggregate into amyloid fibrils has increased considerably during recent years. Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation. Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules. In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood. Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease. This review summarizes current knowledge about AA amyloidosis. The systemic amyloidoses have been regarded as intractable conditions, but improvements in the understanding of fibril composition and pathogenesis over the past decade have led to the development of a number of different therapeutic approaches with promising results.


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Literature Cited

  1. Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G. 1.  et al. 2012. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 19:167–70 [Google Scholar]
  2. Shirahama T, Cohen AS. 2.  1967. High-resolution electron microscopic analysis of the amyloid fibril. J. Cell Biol. 33:679–708 [Google Scholar]
  3. Sunde M, Blake CC. 3.  1998. From the globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q. Rev. Biophys. 31:1–39 [Google Scholar]
  4. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA. 4.  et al. 2007. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447:453–57 [Google Scholar]
  5. Sachse C, Fändrich M, Grigorieff N. 5.  2008. Paired β-sheet structure of an Aβ(1–40) amyloid fibril revealed by electron microscopy. PNAS 105:7462–66 [Google Scholar]
  6. Schmidt M, Sachse C, Richter W, Xu C, Fändrich M, Grigorieff N. 6.  2009. Comparison of Alzheimer Aβ(1–40) and Aβ(1–42) amyloid fibrils reveals similar protofilament structures. PNAS 106:19813–18 [Google Scholar]
  7. Wasmer C, Lange A, Van Melckebeke H, Siemer AB, Riek R, Meier BH. 7.  2008. Amyloid fibrils of the HET-s(218–289) prion form a β solenoid with a triangular hydrophobic core. Science 319:1523–26 [Google Scholar]
  8. Eanes ED, Glenner GG. 8.  1968. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16:673–77 [Google Scholar]
  9. Fändrich M. 9.  2007. On the structural definition of amyloid fibrils and other polypeptide aggregates. Cell. Mol. Life Sci. 64:2066–78 [Google Scholar]
  10. Chiti F, Dobson CM. 10.  2006. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75:333–66 [Google Scholar]
  11. Westermark P. 11.  2005. Aspects on human amyloid forms and their fibril polypeptides. FEBS J. 272:5942–49 [Google Scholar]
  12. Kisilevsky R. 12.  2000. Review: amyloidogenesis—unquestioned answers and unanswered questions. J. Struct. Biol. 130:99–108 [Google Scholar]
  13. Gellermann GP, Appel TR, Tannert A, Radestock A, Hortschansky P. 13.  et al. 2005. Raft lipids as common components of human extracellular amyloid fibrils. PNAS 102:6297–302 [Google Scholar]
  14. Pepys MB. 14.  2006. Amyloidosis. Annu. Rev. Med. 57:223–41 [Google Scholar]
  15. Fowler DM, Koulov AV, Balch WE, Kelly JW. 15.  2007. Functional amyloid—from bacteria to humans. Trends Biochem. Sci. 32:217–24 [Google Scholar]
  16. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE. 16.  2009. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 2009:959–91 [Google Scholar]
  17. Fändrich M. 17.  2012. Oligomeric intermediates in amyloid formation: structure determination and mechanisms of toxicity. J. Mol. Biol. 421:427–40 [Google Scholar]
  18. Azevedo EP, Pereira HM, Garratt RC, Kelly JW, Foguel D, Palhano FL. 18.  2011. Dissecting the structure, thermodynamic stability, and aggregation properties of the A25T transthyretin (A25T-TTR) variant involved in leptomeningeal amyloidosis: identifying protein partners that co-aggregate during A25T-TTR fibrillogenesis in cerebrospinal fluid. Biochemistry 50:11070–83 [Google Scholar]
  19. Lansbury PT Jr. 19.  1999. Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. PNAS 96:3342–44 [Google Scholar]
  20. Ben-Zvi I, Livneh A. 20.  2011. Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat. Rev. Rheumatol. 7:105–12 [Google Scholar]
  21. Lane T, Loeffler JM, Rowczenio DM, Gilbertson JA, Bybee A. 21.  et al. 2013. AA amyloidosis complicating the hereditary periodic fever syndromes. Arthritis Rheum. 65:1116–21 [Google Scholar]
  22. Booth DR, Booth SE, Gillmore JD, Hawkins PN, Pepys MB. 22.  1998. SAA1 alleles as risk factors in reactive systemic AA amyloidosis. Amyloid 5:262–65 [Google Scholar]
  23. Baba S, Masago SA, Takahashi T, Kasama T, Sugimura H. 23.  et al. 1995. A novel allelic variant of serum amyloid A, SAA1γ: genomic evidence, evolution, frequency, and implication as a risk factor for reactive systemic AA-amyloidosis. Hum. Mol. Genet. 4:1083–87 [Google Scholar]
  24. Moriguchi M, Terai C, Kaneko H, Koseki Y, Kajiyama H. 24.  et al. 2001. A novel single-nucleotide polymorphism at the 5′-flanking region of SAA1 associated with risk of type AA amyloidosis secondary to rheumatoid arthritis. Arthritis Rheum. 44:1266–72 [Google Scholar]
  25. Yamada T, Okuda Y, Takasugi K, Wang L, Marks D. 25.  et al. 2003. An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians. Amyloid 10:7–11 [Google Scholar]
  26. Murphy CL, Wang S, Kestler DP, Stevens FA, Weiss DT, Solomon A. 26.  2009. AA amyloidosis associated with a mutated serum amyloid A4 protein. Amyloid 16:84–88 [Google Scholar]
  27. McCubbin WD, Kay CM, Narindrasorasak S, Kisilevsky R. 27.  1988. Circular-dichroism studies on two murine serum amyloid A proteins. Biochem. J. 256:775–83 [Google Scholar]
  28. Noborn F, O'Callaghan P, Hermansson E, Zhang X, Ancsin JB. 28.  et al. 2011. Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein. PNAS 108:5584–89 [Google Scholar]
  29. Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A. 29.  et al. 2010. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 468:93–97 [Google Scholar]
  30. Lindquist SL, Kelly JW. 30.  2011. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Cold Spring Harb. Perspect. Biol. 3:a004507 [Google Scholar]
  31. Taylor RC, Dillin A. 31.  2011. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 3:a004440 [Google Scholar]
  32. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C. 32.  2010. Widespread protein aggregation as an inherent part of aging in C. elegans. PLOS Biol. 8:e1000450 [Google Scholar]
  33. Oza VB, Smith C, Raman P, Koepf EK, Lashuel HA. 33.  et al. 2002. Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors. J. Med. Chem. 45:321–32 [Google Scholar]
  34. Zhao L, Buxbaum JN, Reixach N. 34.  2013. Age-related oxidative modifications of transthyretin modulate its amyloidogenicity. Biochemistry. 52:1913–26 [Google Scholar]
  35. Jarrett JT, Lansbury PT. 35.  1993. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?. Cell 73:1055–58 [Google Scholar]
  36. Sachse C, Grigorieff N, Fändrich M. 36.  2010. Nanoscale flexibility parameters of Alzheimer amyloid fibrils determined by electron cryo-microscopy. Angew. Chem. Int. Ed. Engl. 49:1321–23 [Google Scholar]
  37. Haass C, Selkoe DJ. 37.  2007. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8:101–12 [Google Scholar]
  38. Hebda JA, Miranker AD. 38.  2009. The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes. Annu. Rev. Biophys. 38:125–52 [Google Scholar]
  39. Bolognesi B, Kumita JR, Barros TP, Esbjorner EK, Luheshi LM. 39.  et al. 2010. ANS binding reveals common features of cytotoxic amyloid species. ACS Chem. Biol. 20:735–40 [Google Scholar]
  40. Reixach N, Deechongkit S, Jiang X, Kelly JW, Buxbaum JN. 40.  2004. Tissue damage in the amyloidoses: transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. PNAS 101:2817–22 [Google Scholar]
  41. Smith AM, Jahn TR, Ashcroft AE, Radford SE. 41.  2006. Direct observation of oligomeric species formed in the early stages of amyloid fibril formation using electrospray ionisation mass spectrometry. J. Mol. Biol. 364:9–19 [Google Scholar]
  42. Westermark P, Andersson A, Westermark GT. 42.  2011. Islet amyloid polypeptide, islet amyloid and diabetes mellitus. Physiol. Rev. 91:795–826 [Google Scholar]
  43. Zraika S, Hull RL, Verchere CB, Clark A, Potter KJ. 43.  et al. 2010. Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?. Diabetologia 53:1046–56 [Google Scholar]
  44. Laganowsky A, Liu C, Sawaya MR, Whitelegge JP, Park J. 44.  et al. 2012. Atomic view of a toxic amyloid small oligomer. Science 335:1228–31 [Google Scholar]
  45. Wang Y, Srinivasan S, Ye Z, Javier Aguilera J, Lopez MM, Colón W. 45.  2011. Serum amyloid A 2.2 refolds into a octameric oligomer that slowly converts to a more stable hexamer. Biochem. Biophys. Res. Commun. 407:725–29 [Google Scholar]
  46. Yu J, Zhu H, Guo JT, de Beer FC, Kindy MS. 46.  2000. Expression of mouse apolipoprotein SAA1.1 in CE/J mice: isoform-specific effects on amyloidogenesis. Lab. Investig. 80:1797–806 [Google Scholar]
  47. Mori M, Tiang G, Higuchi K. 47.  2014. AA amyloidosis–resistant CE/J mice have Saa1 and Saa2 genes that encode an identical SAA isoform. Amyloid 21:1–8 [Google Scholar]
  48. Senthilkumar S, Chang E, Jayakumar R. 48.  2008. Diffusible amyloid oligomers trigger systemic amyloidosis in mice. Biochem. J. 415:207–15 [Google Scholar]
  49. Westermark P, Nilsson GT. 49.  1984. Demonstration of amyloid protein A in old museum specimens. Arch. Pathol. Lab. Med. 108:217–19 [Google Scholar]
  50. Mutru O, Laakso M, Isomäki H, Koota K. 50.  1985. Ten years mortality and causes of death in patients with rheumatoid arthritis. Br. Med. J. 290:1797–99 [Google Scholar]
  51. Okuda Y, Ohnishi M, Matoba K, Jouyama K, Yamada A. 51.  et al. 2014. Comparison of the clinical utility of tocilizumab and anti-TNF therapy in AA amyloidosis complicating rheumatic diseases. Mod. Rheumatol. 24:137–43 [Google Scholar]
  52. Hazenberg BP, van Rijswijk MH. 52.  2000. Where has secondary amyloid gone?. Ann. Rheum. Dis. 59:577–79 [Google Scholar]
  53. Immonen K, Finne P, Grönhagen-Riska C, Pettersson T, Klaukka T. 53.  et al. 2011. A marked decline in the incidence of renal replacement therapy for amyloidosis associated with inflammatory rheumatic diseases—data from nationwide registries in Finland. Amyloid 18:25–28 [Google Scholar]
  54. McAdam KP, Raynes JG, Alpers MP, Westermark GT, Westermark P. 54.  1996. Amyloidosis: a global problem common in Papua New Guinea. P.N.G. Med. J. 39:284–96 [Google Scholar]
  55. Bunker D, Gorevic P. 55.  2012. AA amyloidosis: Mount Sinai experience 1997–2012. Mt. Sinai J. Med. 79:749–56 [Google Scholar]
  56. Husby G, Marhaug G, Dowton B, Sletten K, Sipe JD. 56.  1994. Serum amyloid A (SAA): biochemistry, genetics and the pathogenesis of AA amyloidosis. Amyloid 1:119–37 [Google Scholar]
  57. Kisilevsky R, Manley PN. 57.  2012. Acute-phase serum amyloid A: perspectives on its physiological and pathological roles. Amyloid 19:5–14 [Google Scholar]
  58. Yoshizaki K. 58.  2011. Pathogenic role of IL-6 combined with TNF-α or IL-1 in the induction of acute phase proteins SAA and CRP in chronic inflammatory diseases. Adv. Exp. Med. Biol. 691:141–50 [Google Scholar]
  59. Santiago P, Roig-Lopez JL, Santiago C, Garcia-Arraras JE. 59.  2000. Serum amyloid A protein in an echinoderm: its primary structure and expression during intestinal regeneration in the sea cucumber Holothuria glaberrima. J. Exp. Zool. 288:335–44 [Google Scholar]
  60. Lu J, Yu Y, Zhu I, Cheng Y, Sun PD. 60.  2014. Structural mechanism of serum amyloid A–mediated inflammatory amyloidosis. PNAS 111:5189–94 [Google Scholar]
  61. Srinivasan S, Patke S, Wang Y, Ye Z, Litt J. 61.  et al. 2013. Pathogenic serum amyloid A 1.1 shows a long oligomer-rich fibrillation lag phase contrary to the highly amyloidogenic non-pathogenic SAA2.2. J. Biol. Chem. 288:2744–55 [Google Scholar]
  62. Snow AD, Bramson R, Mar H, Wight TN, Kisilevsky R. 62.  1991. A temporal and ultrastructural relationship between heparan sulfate proteoglycans and AA amyloid in experimental amyloidosis. J. Histochem. Cytochem. 39:1321–30 [Google Scholar]
  63. Noborn F, Ancsin JB, Ubhayasekera W, Kisilevsky R, Li JP. 63.  2012. Heparan sulfate dissociates serum amyloid A (SAA) from acute-phase high-density lipoprotein, promoting SAA aggregation. J. Biol. Chem. 287:25669–77 [Google Scholar]
  64. Shirahama T, Cohen AS. 64.  1975. Intralysosomal formation of amyloid fibrils. Am. J. Pathol. 81:101–16 [Google Scholar]
  65. Elimova E, Kisilevsky R, Ancsin JB. 65.  2009. Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch. FASEB J. 23:3436–48 [Google Scholar]
  66. Ishii W, Liepnieks JJ, Yamada T, Benson MD, Kluve-Beckerman B. 66.  2013. Human SAA1-derived amyloid deposition in cell culture: a consistent model utilizing human peripheral blood mononuclear cells and serum-free medium. Amyloid 20:61–71 [Google Scholar]
  67. Lundmark K, Vahdat Shariatpanahi A, Westermark GT. 67.  2013. Depletion of spleen macrophages delays AA amyloid development: a study performed in the rapid mouse model of AA amyloidosis. PLOS ONE 8:e79104 [Google Scholar]
  68. Kennel SJ, Macy S, Wooliver C, Huang Y, Richey T. 68.  et al. 2014. Phagocyte depletion inhibits AA amyloid accumulation in AEF-induced huIL-6 transgenic mice. Amyloid 21:45–53 [Google Scholar]
  69. Kisilevsky R, Boudreau L. 69.  1983. Kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy. Lab. Investig. 48:53–59 [Google Scholar]
  70. Kluve-Beckerman B, Manaloor J, Liepnieks JJ. 70.  2001. Binding, trafficking and accumulation of serum amyloid A in peritoneal macrophages. Scand. J. Immunol. 53:393–400 [Google Scholar]
  71. Yamada T, Liepnieks JJ, Kluve-Beckerman B, Benson MD. 71.  1995. Cathepsin B generates the most common form of amyloid A (76 residues) as a degradation product from serum amyloid A. Scand. J. Immunol. 41:94–97 [Google Scholar]
  72. Chronopoulos S, Laird DW, Ali-Khan Z. 72.  1994. Immunolocalization of serum amyloid A and AA amyloid in lysosomes in murine monocytoid cells: confocal and immunogold electron microscopic studies. J. Pathol. 173:361–69 [Google Scholar]
  73. Stix B, Kähne T, Sletten K, Raynes J, Roessner A, Röcken C. 73.  2001. Proteolysis of AA amyloid fibril proteins by matrix metalloproteinases-1, -2, and -3. Am. J. Pathol. 159:561–70 [Google Scholar]
  74. van der Hilst JC, Yamada T, Op den Kamp HJ, van der Meer JW, Drenth JP, Simon A. 74.  2008. Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis. Rheumatology 47:1651–54 [Google Scholar]
  75. Nyström SN, Westermark GT. 75.  2012. AA-amyloid is cleared by endogenous immunological mechanisms. Amyloid 19:138–45 [Google Scholar]
  76. Maury CP, Teppo AM. 76.  1988. Antibodies to amyloid A protein in rheumatic diseases. Rheumatol. Int. 8:107–11 [Google Scholar]
  77. Magy N, Benson MD, Liepnieks JJ, Kluve-Beckerman B. 77.  2007. Cellular events associated with the initial phase of AA amyloidogenesis: insights from a human monocyte model. Amyloid 14:51–63 [Google Scholar]
  78. Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J. 78.  et al. 2002. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295:851–55 [Google Scholar]
  79. Scheibel T, Lindquist SL. 79.  2001. The role of conformational flexibility in prion propagation and maintenance for Sup35p. Nat. Struct. Biol. 8:958–62 [Google Scholar]
  80. Lundmark K, Westermark GT, Olsén A, Westermark P. 80.  2005. Protein fibrils in nature can enhance AA amyloidosis in mice: cross-seeding as a disease mechanism. PNAS 102:6098–102 [Google Scholar]
  81. Westermark P, Lundmark K, Westermark GT. 81.  2009. Fibrils from designed non-amyloid-related synthetic peptides induce AA-amyloidosis during inflammation in an animal model. PLOS ONE 4:e6041 [Google Scholar]
  82. Ranløv P. 82.  1967. The adoptive transfer of experimental mouse amyloidosis by intravenous injections of spleen cell extracts from casein-treated syngeneic donor mice. Acta Pathol. Microbiol. Scand. 70:321–35 [Google Scholar]
  83. Janigan DT, Druet RL. 83.  1968. Experimental murine amyloidosis in X-irradiated recipients of spleen homogenates or serum from sensitized donors. Am. J. Pathol. 52:381–90 [Google Scholar]
  84. Hardt F. 84.  1971. Transfer amyloidosis. Am. J. Pathol. 65:411–24 [Google Scholar]
  85. Gajdusek DC, Gibbs CJ Jr, Alpers M. 85.  1966. Experimental transmission of a kuru-like syndrome to chimpanzees. Nature 209:794–96 [Google Scholar]
  86. Johan K, Westermark G, Engström U, Gustavsson Å, Hultman P, Westermark P. 86.  1998. Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils. PNAS 95:2558–63 [Google Scholar]
  87. Lundmark K, Westermark GT, Nyström S, Murphy CL, Solomon A, Westermark P. 87.  2002. Transmissibility of systemic amyloidosis by a prion-like mechanism. PNAS 99:6979–84 [Google Scholar]
  88. Yan J, Fu X, Ge F, Zhang B, Yao J. 88.  et al. 2007. Cross-seeding and cross-competition in mouse apolipoprotein A-II amyloid fibrils and protein A amyloid fibrils. Am. J. Pathol. 171:172–80 [Google Scholar]
  89. Sörby R, Espenes A, Landsverk T, Westermark G. 89.  2008. Rapid induction of experimental AA amyloidosis in mink by intravenous injection of amyloid enhancing factor. Amyloid 15:20–28 [Google Scholar]
  90. Murakami T, Naeem M, Inoshima Y, Yanai T, Goryo M, Ishiguro N. 90.  2013. Experimental induction oral transmission of avian AA amyloidosis in vaccinated white hens. Amyloid 20:80–85 [Google Scholar]
  91. Zhang B, Une Y, Fu X, Yan J, Ge F. 91.  et al. 2008. Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. PNAS 105:7263–68 [Google Scholar]
  92. Cui D, Kawano H, Takahashi M, Hoshii Y, Setoguchi M. 92.  et al. 2002. Acceleration of murine AA amyloidosis by oral administration of amyloid fibrils extracted from different species. Pathol. Int. 52:40–45 [Google Scholar]
  93. Solomon A, Richey T, Murphy CL, Weiss DT, Wall JS. 93.  et al. 2007. Amyloidogenic potential of foie gras. PNAS 104:10998–1001 [Google Scholar]
  94. Yoshida T, Zhang P, Fu X, Higuchi K, Ikeda SI. 94.  2009. Slaughtered aged cattle might be one dietary source exhibiting amyloid enhancing factor activity. Amyloid 16:25–31 [Google Scholar]
  95. Shirahama T, Cohen AS. 95.  1980. Redistribution of amyloid deposits. Am. J. Pathol. 99:539–50 [Google Scholar]
  96. Enqvist S, Sletten K, Stevens FJ, Hellman U, Westermark P. 96.  2007. Germ line origin and somatic mutations determine the target tissues in systemic AL-amyloidosis. PLOS ONE 2:e981 [Google Scholar]
  97. Levin M, Franklin EC, Frangione B, Pras M. 97.  1972. The amino acid sequence of a major nonimmunoglobulin component of some amyloid fibrils. J. Clin. Investig. 51:2773–76 [Google Scholar]
  98. Sletten K, Husby G. 98.  1974. The complete amino-acid sequence of non-immunoglobulin amyloid fibril protein AS in rheumatoid arthritis. Eur. J. Biochem. 41:117–25 [Google Scholar]
  99. Westermark P, Sletten K, Eriksson M. 99.  1979. Morphologic and chemical variation of the kidney lesions in amyloidosis secondary to rheumatoid arthritis. Lab. Investig. 41:427–31 [Google Scholar]
  100. Westermark GT, Sletten K, Westermark P. 100.  1983. Massive vascular AA-amyloidosis: a histologically and biochemically distinctive subtype of reactive systemic amyloidosis. Scand. J. Immunol. 30:605–13 [Google Scholar]
  101. Falck HM, Törnroth T, Wegelius O. 101.  1983. Predominantly vascular amyloid deposition in the kidney in patients with minimal or no proteinuria. Clin. Nephrol. 19:137–42 [Google Scholar]
  102. Westermark GT, Sletten K, Grubb A, Westermark P. 102.  1990. AA-amyloidosis: tissue component–specific association of various protein AA subspecies and evidence of a fourth SAA gene product. Am. J. Pathol. 137:377–83 [Google Scholar]
  103. Westermark GT, Westermark P, Sletten K. 103.  1987. Amyloid fibril protein AA: characterization of uncommon subspecies from a patient with rheumatoid arthritis. Lab. Investig. 57:57–64 [Google Scholar]
  104. Tanaka M, Chien P, Naber N, Cooke RA, Weissmann JS. 104.  2004. Conformational variations in an infectious protein determine prion strain differences. Nature 428:323–28 [Google Scholar]
  105. Wadsworth JDF, Joiner S, Linehan JM, Asante EA, Brandner S, Collinge J. 105.  2008. The origin of the prion agent of kuru: molecular and biological strain typing. Philos. Trans. R. Soc. B 363:3747–53 [Google Scholar]
  106. Colby DW, Giles K, Legname G, Wille H, Baskakov IV. 106.  et al. 2009. Design and construction of diverse mammalian prion strains. PNAS 106:20417–22 [Google Scholar]
  107. Makarava N, Baskakov IV. 107.  2008. The same primary structure of the prion protein yields two distinct self-propagating states. J. Biol. Chem. 283:15988–96 [Google Scholar]
  108. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R. 108.  2005. Self-propagating, molecular-level polymorphism in Alzheimer's β-amyloid fibrils. Science 307:262–65 [Google Scholar]
  109. Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH. 109.  et al. 2013. Structural and functional characterization of two α-synuclein strains. Nat. Commun. 4:2575 [Google Scholar]
  110. Westermark GT, Westermark P. 110.  2010. Prion-like aggregates: infectious agents in human disease. Trends Mol. Med. 16:501–7 [Google Scholar]
  111. Westermark P. 111.  2012. Subcutaneous adipose tissue biopsy for amyloid protein studies. Methods Mol. Biol. 849:363–711 [Google Scholar]
  112. Nilsson KP, Hammarström P, Ahlgren F, Herland A, Schnell EA. 112.  et al. 2006. Conjugated polyelectrolytes—conformation-sensitive optical probes for staining and characterization of amyloid deposits. ChemBioChem 7:1096–104 [Google Scholar]
  113. Nilsson KP, Ikenberg K, Aslund A, Fransson S, Konradsson P. 113.  et al. 2010. Structural typing of systemic amyloidoses by luminescent-conjugated polymer spectroscopy. Am. J. Pathol. 176:563–74 [Google Scholar]
  114. Hawkins PN, Lavender JP, Pepys MB. 114.  1990. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N. Engl. J. Med. 323:508–13 [Google Scholar]
  115. Hawkins PN, Vigushin DM, Kelsey CR, Gray RES, Hall MA. 115.  et al. 1993. Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis. Arthritis Rheum. 36:842–51 [Google Scholar]
  116. Wall JS, Richey T, Stuckey AC, Donnell RL, Macy SD. 116.  et al. 2011. In vivo molecular imaging of peripheral amyloidosis using heparin-binding peptides. PNAS 108:13899–900 [Google Scholar]
  117. Antoni G, Lubberink M, Estrada S, Axelsson J, Carlson K. 117.  et al. 2013. In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET. J. Nucl. Med. 54:213–20 [Google Scholar]
  118. Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA. 118.  et al. 2002. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N. Engl. J. Med. 346:1786–91 [Google Scholar]
  119. Schönland SO, Hegenbart U, Bochtler T, Mangatter A, Hansberg M. 119.  et al. 2012. Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. Blood 119:488–93 [Google Scholar]
  120. Linke RP, Oos R, Wiegel NM, Nathrath WB. 120.  2006. Classification of amyloidosis: misdiagnosing by way of incomplete immunohistochemistry and how to prevent it. Acta Histochem. 108:197–208 [Google Scholar]
  121. Westermark P, Davey E, Lindbom K, Enqvist S. 121.  2006. Subcutaneous fat tissue for diagnosis and studies of systemic amyloidosis. Acta Histochem. 108:209–13 [Google Scholar]
  122. Arbustini E, Verga L, Concardi M, Palladini G, Obici L, Merlini G. 122.  2002. Electron and immuno-electron microscopy of abdominal fat identifies and characterizes amyloid fibrils in suspected cardiac amyloidosis. Amyloid 9:108–14 [Google Scholar]
  123. Murphy CL, Wang S, Williams T, Weiss DT, Solomon A. 123.  2006. Characterization of systemic amyloid deposits by mass spectrometry. Methods Enzymol. 412:48–62 [Google Scholar]
  124. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR III, Dogan A. 124.  2009. Classification of amyloidosis by laser microdissection and mass spectrometry–based proteomic analysis in clinical biopsy specimens. Blood 114:4957–59 [Google Scholar]
  125. Lavatelli F, Vrana JA. 125.  2011. Proteomic typing of amyloid deposits in systemic amyloidosis. Amyloid 18:177–82 [Google Scholar]
  126. Waldenström H. 126.  1928. On the formation and disappearance of amyloid in man. Acta Chir. Scand. 63:479–530 [Google Scholar]
  127. Tennent GA, Lovat LB, Pepys MB. 127.  1995. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. PNAS 92:4299–303 [Google Scholar]
  128. O'Nuallain B, Wetzel R. 128.  2002. Conformational Abs recognizing a generic amyloid fibril epitope. PNAS 99:1485–90 [Google Scholar]
  129. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC. 129.  et al. 2003. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–89 [Google Scholar]
  130. Solomon A, Weiss DT, Wall JS. 130.  2003. Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies. Cancer Biother. Radiopharm. 18:853–60 [Google Scholar]
  131. Wall JS, Kennel SJ, Stuckey AC, Long MJ, Townsend DW. 131.  et al. 2010. Radioimmunodetection of amyloid deposits in patients with AL amyloidosis. Blood 116:2241–44 [Google Scholar]
  132. Solomon A, Weiss DT, Wall JS. 132.  2003. Therapeutic potential of chimeric amyloid-reactive monoclonal antibody 11-1F4. Clin. Cancer Res. 9:3831S–38S [Google Scholar]
  133. O'Nuallain B, Hrncic R, Wall JS, Weiss DT, Solomon A. 133.  2006. Diagnostic and therapeutic potential of amyloid-reactive IgG antibodies contained in human sera. J. Immunol. 176:7071–78 [Google Scholar]
  134. Li JP, Galvis ML, Gong F, Zhang X, Zcharia E. 134.  et al. 2005. In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis. PNAS 102:6473–77 [Google Scholar]
  135. Ancsin JB, Kisilevsky R. 135.  1999. The heparin/heparan sulfate–binding site on apo–serum amyloid A: implications for the therapeutic intervention of amyloidosis. J. Biol. Chem. 274:7172–81 [Google Scholar]
  136. Egashira M, Takase H, Yamamoto I, Tanaka M, Saito H. 136.  2011. Identification of regions responsible for heparin-induced amyloidogenesis of human serum amyloid A using its fragment peptides. Arch. Biochem. Biophys. 511:101–6 [Google Scholar]
  137. Westermark GT, Engström U, Westermark P. 137.  1992. The N-terminal segment of protein AA determines its fibrillogenic property. Biochem. Biophys. Res. Commun. 182:27–33 [Google Scholar]
  138. Kisilevsky R, Lemieux LJ, Fraser PE, Kong X, Hultin PG, Szarek WA. 138.  1995. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease. Nat. Med. 1:143–48 [Google Scholar]
  139. Dember LM, Hawkins PN, Hazenberg BP, Gorevic PD, Merlini G. 139.  et al. 2007. Eprodisate for the treatment of renal disease in AA amyloidosis. N. Engl. J. Med. 356:2349–60 [Google Scholar]
  140. Kluve-Beckerman B, Hardwick J, Du L, Benson MD, Monia BP. 140.  et al. 2011. Antisense oligonucleotide suppression of serum amyloid A reduces amyloid deposition in mice with AA amyloidosis. Amyloid 18:136–46 [Google Scholar]
  141. Benson MD, Kluve-Beckerman B, Zeldenrust SR, Siesky AM, Bodenmiller DM. 141.  et al. 2006. Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33:609–18 [Google Scholar]
  142. Benson MD, Smith RA, Hung G, Kluve-Beckerman B, Showalter AD. 142.  et al. 2010. Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment. Amyloid 17:43–49 [Google Scholar]
  143. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN. 142a.  et al. 2013. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med 369:819–29 [Google Scholar]
  144. McCutchen SL, Colon W, Kelly JW. 143.  1993. Transthyretin mutation Leu-55-Pro significantly alters tetramer stability and increases amyloidogenicity. Biochemistry 16:12119–27 [Google Scholar]
  145. Miroy GJ, Lai Z, Lashuel HA, Peterson SA, Strang C, Kelly JW. 144.  1996. Inhibiting transthyretin amyloid fibril formation via protein stabilization. PNAS 93:15051–56 [Google Scholar]
  146. Sekijima Y, Dendle MA, Kelly JW. 145.  2006. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 13:236–49 [Google Scholar]
  147. Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW. 146.  2012. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J. Mol. Biol. 421:185–203 [Google Scholar]
  148. Palha JA, Ballinari D, Amboldi N, Cardoso I, Fernandes R. 147.  et al. 2000. 4′-Iodo-4′-deoxydoxorubicin disrupts the fibrillar structure of transthyretin amyloid. Am. J. Pathol. 156:1919–25 [Google Scholar]
  149. Gertz MA, Lacy MQ, Dispenzieri A, Cheson BD, Barlogie B. 148.  et al. 2002. A multicenter phase II trial of 4′-iodo-4′-deoxydoxorubicin (IDOX) in primary amyloidosis (AL). Amyloid 9:24–30 [Google Scholar]
  150. Cardoso I, Merlini G, Saraiva MJ. 149.  2003. 4′-Iodo-4′-deoxydoxorubicin and tetracycline's disrupt transthyretin amyloid fibrils in vitro producing nontoxic species: screening for TTR fibril disrupters. FASEB J. 17:803–9 [Google Scholar]
  151. Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G. 150.  et al. 2014. Nomenclature 2014: amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 21:221–24 [Google Scholar]

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