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Studies on Pathogenesis of Experimental AA Amyloidosis: Effects of Amyloid Enhancing Factor and Amyloid-Like Fibrils in Rapid Amyloid Induction
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-28606Local ID: 13761ISBN: 91-7373-152-8 (print)OAI: oai:DiVA.org:liu-28606DiVA: diva2:249417
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
List of papers
1. Fibrils from Synthetic Amyloid-Related Peptides Enhance Development of Experimental AA-Amyloidosis in Mice
Open this publication in new window or tab >>Fibrils from Synthetic Amyloid-Related Peptides Enhance Development of Experimental AA-Amyloidosis in Mice
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1994 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 199, no 1, 306-312 p.Article in journal (Refereed) Published
Abstract [en]

Amyloid enhancing factor is an incompletely characterized activity of extracts from many amyloid-containing tissues and which greatly shortens the preamyloidotic phase during experimental induction of AA-amyloidosis. In this communication we show that amyloid-like fibrils made in vitro from synthetic peptides, corresponding to segments of amyloid fibril proteins, have amyloid enhancing factor-like activity. Thus, there is a possibility that amyloid enhancing factor activity depends on small fibrils serving as nucleation centers for fibril elongation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80889 (URN)10.1006/bbrc.1994.1229 (DOI)
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
2. Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils
Open this publication in new window or tab >>Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80890 (URN)
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
3. Transmissibility of systemic amyloidosis by a prion-like mechanism
Open this publication in new window or tab >>Transmissibility of systemic amyloidosis by a prion-like mechanism
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2002 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 10, 6979-6984 p.Article in journal (Refereed) Published
Abstract [en]

The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20805 (URN)10.1073/pnas.092205999 (DOI)12011456 (PubMedID)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2012-09-03Bibliographically approved
4. Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
Open this publication in new window or tab >>Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
(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
Identifiers
urn:nbn:se:liu:diva-80892 (URN)
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2012-09-03Bibliographically approved

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Lundmark, Katarzyna

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