title: Pathogenetic mechanisms of amyloid A amyloidosis.
abstract: Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.
authors: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, United Kingdom.
authors: J Paul
authors: JP
authors: Simons
authors: Raya
authors: R
authors: Al-Shawi
authors: Stephan
authors: S
authors: Ellmerich
authors: Ivana
authors: I
authors: Speck
authors: Samrina
authors: S
authors: Aslam
authors: Winston L
authors: WL
authors: Hutchinson
authors: Palma P
authors: PP
authors: Mangione
authors: Petra
authors: P
authors: Disterer
authors: Janet A
authors: JA
authors: Gilbertson
authors: Toby
authors: T
authors: Hunt
authors: David J
authors: DJ
authors: Millar
authors: Shane
authors: S
authors: Minogue
authors: Karl
authors: K
authors: Bodin
authors: Mark B
authors: MB
authors: Pepys
authors: Philip N
authors: PN
authors: Hawkins
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D003224:Congo Red; D017931:DNA Primers / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000150:complications*; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D017931:DNA Primers; D000685:Serum Amyloid A Protein; D003224:Congo Red; D004318:Doxycycline
keywords: 3Rs; disease model
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