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Transmissibility of systemic amyloidosis by a prion-like mechanism
Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, TN 37996, USA.
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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.

Place, publisher, year, edition, pages
2002. Vol. 99, no 10, 6979-6984 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-20805DOI: 10.1073/pnas.092205999PubMedID: 12011456OAI: oai:DiVA.org:liu-20805DiVA: diva2:236161
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Deposition and Resolution of AA Amyloid
Open this publication in new window or tab >>Deposition and Resolution of AA Amyloid
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloidosis is a group of protein misfolding diseases characterized by extracellulardeposition of fibrillar protein aggregates. Today more than 25 different human amyloidogenicproteins have been identified, causing a variety of pathological conditions that includeAlzheimer’s disease, type 2 diabetes and prion diseases. Amyloid A (AA) amyloidosis is acomplication to long standing inflammatory disorders and amyloid is formed from N-terminalfragments of the acute phase protein serum amyloid A. AA amyloidosis developsspontaneously in many mice strains in response to inflammatory stimulation. Amyloidformation is nucleation dependent and develops after a lag phase of months. If an extract fromamyloid loaded tissue is administered to the animal, the lag phase is shortened to days. Thetissue extract is referred to as amyloid enhancing factor, AEF.

In paper I we demonstrate that the active component of AEF is the amyloid fibril itself. We doalso show that AEF retains its activity over a long period of time and is active in very low(femtomolar) doses. AEF activity can be transmitted in a serial manner, also by oraladministration. Thus, AEF shares several characteristics with the infectious prion protein. Wetherefore suggest that AEF induces protein conformational changes in a prion like manner andthat experimental AA amyloidosis is a transmissible disease.

In paper II we showed that peripheral blood monocytes recovered from mice with AAamyloidosis carry AEF activity but plasma does not. AA amyloid was detected in occasionalmonocytes. It is possible that these fibrils serve as seeds or nuclei for conformational changesand subsequent amyloid deposition in the recipient animal.

In paper III mechanisms of amyloid clearance in experimental AA amyloidosis were studied.During amyloid clearance antibodies directed against AA were detected. Immunoglobulinsdid also co-localize with AA deposits. Amyloid fibrils were detected intracellular inmacrophages. These findings suggest that immune mechanisms contribute to AA amyloidclearance in mice and that macrophages are key players in the process. Immunoglobulins mayserve as opsonins facilitating phagocytosis of amyloid.

It is believed that the early stages of amyloidogenesis are common in all forms of amyloiddiseases and that the amyloid formation process is cytotoxic. There are few studies onbiological effects of AA deposition in post mitotic tissue such as the heart. In paper IV weinvestigate the effects of cardiac AA amyloid deposition. Our results indicate that cardiac AAdeposition is associated with increased autophagic activity.

In conclusion this thesis provides new insights to the dynamics of the turnover of AA amyloidand the mechanisms involved. Our results clearly show that the innate capacity of amyloidclearance is efficient.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1105
Keyword
AA-amyloid, autophagy, resolution
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-20292 (URN)978-91-7393-684-2 (ISBN)
Public defence
2009-03-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2009-09-21 Created: 2009-09-02 Last updated: 2012-10-01Bibliographically approved
2. 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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Lundmark, KatarzynaWestermark, Gunilla T.Nyström, Sofia

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