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Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Howard Hughes Medical Institute, University of Chicago, Il, USA.
Department of Genetics and Pathology, Uppsala University, Sweden.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Experimental AA amyloidosis, where the acute phase protein serum AA (SAA) forms amyloid fibrils, can be induced in mice provoked with inflannnatmy challenge. The time for development of amyloid is dramatically shortened when the animals concomitantly receive extract of a tissue from another mouse with amyloid 1-3. The active elusive principle has been named Amyloid Enhancing Factor (AEF) and experimental secondary amyloidosis was supposed to be a nucleation dependent process. The nature of the nucleus, however, was unknown for a long time. Our studies with synthetic amyloid-like fibrils made frmn short amyloidogenic pep tides instead of AEF 4, 5, indicate that the amyloid fibrils theruselves may act as nuclei for fibril formation (Fig. 1a). Here we present the enhanced development of AA -amyloidosis by naturally occurring amyloid-like protein fibrils.

National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-80892OAI: diva2:548993
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2012-09-03Bibliographically 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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 711
National Category
Medical and Health Sciences
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)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-03Bibliographically approved

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