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Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala, Sweden.
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
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1998 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, 2558-2563 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms β-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after ≈25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA–amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

Place, publisher, year, edition, pages
1998. Vol. 95, no 5, 2558-2563 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-80890OAI: oai:DiVA.org:liu-80890DiVA: diva2:548987
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Studies on Pathogenesis of Experimental AA Amyloidosis: Effects of Amyloid Enhancing Factor and Amyloid-Like Fibrils in Rapid Amyloid Induction
Open this publication in new window or tab >>Studies on Pathogenesis of Experimental AA Amyloidosis: Effects of Amyloid Enhancing Factor and Amyloid-Like Fibrils in Rapid Amyloid Induction
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloidosis is a group of diseases, caused by an extracellular deposition of a characteristic proteinaceous material, amyloid, in various organs. Fibril formation occurs in all of amyloid related diseases, making it a crucial mechanism to understand.

Experimental inflammatozy-induced amyloidosis (AA amyloidosis) is proposed to be a nucleation dependent process developing after a lag phase of weeks. The lag phase may be shortened to days by administration of a material extracted from amyloid-loaded tissues. This material is referred to as amyloid enhancing factor (AEF), and is supposed to contain a nucleus that starts fibril formation. However, the nature of this nucleus has not been definitely established.

We have established a murine model of accelerated AA amyloidosis. In this model we have studied amyloid enhancing effects of preparations containing fibrillazy structures extracted from murine amyloid and from amyloid-like fibrils produced in vitro.

Our results show that the murine AEF preparation contains no components other than AA amyloid fibrils and is active infemtomolar doses. This AEF preparation is active when administered orally and retains its activity in animals for months after administration. Amyloid fibrils prepared in vitro from amyloidogenic peptides and certain non amyloidogenic proteins have AEF effect as well. Denaturation of the AA protein in AEF abolishes itsamyloidogenic effect. Nonfibrillazy preparation of amyloidogenic peptide has no AEF effect. Radioiodinated amyloid-like fibrils can be detected in newly formed splenic amyloid, and co-localization of such fibrils with AN/SAA is demonstrated.

Therefore we propose that the active component in AEF is the amyloid fibril itself. The mechanism of nucleation is considered to be similar to the seeded nucleation proposed forprion propagation, in which fibrils, small fibril fragments, or oligomers of scrapie prion protein (PrP) induce profound conformational change in cellular PrP. We propose that experimental AA amyloidosis belongs to the transmissible amyloidoses. The finding that amyloidlike fibrils from naturally occurring nonamyloidogenic proteins act as AEF is of great interest. Ingestion or inhalation of such fibrils may introduce seeds that can start the nucleation process in individuals with elevated SAA levels. Hypothetically, this may explain why only a fraction of patients with longstanding inflammatozy conditions develop amyloid deposits and may implicate environmental factors as important risk factors for AA amyloidosis.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 81 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 711
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28606 (URN)13761 (Local ID)91-7373-152-8 (ISBN)13761 (Archive number)13761 (OAI)
Public defence
2001-12-13, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-03Bibliographically approved

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Johan, KatarzynaWestermark, GunillaHultman, Per

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