Pathogenetic mechanisms of amyloid A amyloidosis

Pathogenetic mechanisms of amyloid A amyloidosis

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 yea...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 40; pp. 16115 - 16120
Main Authors: Simons, J. Paul, Al-Shawib, Raya, Ellmerich, Stephan, Speck, Ivana, Aslam, Samrina, Hutchinson, Winston L., Mangione, Palma P., Disterer, Petra, Gilbertson, Janet A., Hunt, Toby, Millar, David J., Minogue, Shane, Bodin, Karl, Pepys, Mark B., Hawkins, Philip N.
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 01-10-2013
NATIONAL ACADEMY OF SCIENCES
National Acad Sciences
Subjects:
Amyloid - metabolism
Amyloid plaque
Amyloidosis
Amyloidosis - etiology
Amyloidosis - physiopathology
Amyloids
Animals
Biological Sciences
Congo Red
DNA Primers - genetics
Doxycycline - pharmacology
Female
Gene expression
Gene Expression Regulation - drug effects
Genetics
Inflammation
Inflammation - complications
Kidney diseases
Kidneys
Liver
Mice
Mice, Transgenic
Pathogenesis
Potable water
Proteins
Real-Time Polymerase Chain Reaction
Rodents
Serum Amyloid A Protein - metabolism
Spleen
Transgenic animals
3Rs
disease model
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Summary: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.
Bibliography:http://dx.doi.org/10.1073/pnas.1306621110
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Edited* by David J. Weatherall, University of Oxford, Oxford, United Kingdom, and approved July 17, 2013 (received for review April 16, 2013)
Author contributions: J.P.S., R.A.-S., S.E., M.B.P., and P.N.H. designed research; J.P.S., R.A.-S., S.E., I.S., S.A., W.L.H., P.P.M., P.D., J.A.G., T.H., D.J.M., S.M., and K.B. performed research; J.P.S., R.A.-S., S.E., I.S., S.A., W.L.H., P.P.M., P.D., J.A.G., T.H., D.J.M., S.M., K.B., M.B.P., and P.N.H. analyzed data; and J.P.S. and M.B.P. wrote the paper.
2Present address: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1306621110