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AA-amyloidosis can be transferred by peripheral blood monocytes
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.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2008 (English)In: PloS one, ISSN 1932-6203, Vol. 3, no 10, e3308- p.Article in journal (Refereed) Published
Abstract [en]

Spongiform encephalopathies have been reported to be transmitted by blood transfusion even prior to the clinical onset. Experimental AA-amyloidosis shows similarities with prion disease and amyloid-containing organ-extracts can prime a recipient for the disease. In this systemic form of amyloidosis N-terminal fragments of the acute-phase reactant apolipoprotein serum amyloid A are the main amyloid protein. Initial amyloid deposits appear in the perifollicular region of the spleen, followed by deposits in the liver. We used the established murine model and induced AA-amyloidosis in NMRI mice by intravenous injections of purified amyloid fibrils ('amyloid enhancing factor') combined with inflammatory challenge (silver nitrate subcutaneously). Blood plasma and peripheral blood monocytes were isolated, sonicated and re-injected into new recipients followed by an inflammatory challenge during a three week period. When the animals were sacrificed presence of amyloid was analyzed in spleen sections after Congo red staining. Our result shows that some of the peripheral blood monocytes, isolated from animals with detectable amyloid, contained amyloid-seed that primed for AA-amyloid. The seeding material seems to have been phagocytosed by the cells since the AA-precursor (SAA1) was found not be expressed by the monocytes. Plasma recovered from mice with AA amyloidosis lacked seeding capacity. Amyloid enhancing activity can reside in monocytes recovered from mice with AA-amyloidosis and in a prion-like way trigger amyloid formation in conjunction with an inflammatory disorder. Human AA-amyloidosis resembles the murine form and every individual is expected to be exposed to conditions that initiate production of the acute-phase reactant. The monocyte-transfer mechanism should be eligible for the human disease and we point out blood transfusion as a putative route for transfer of amyloidosis.

Place, publisher, year, edition, pages
2008. Vol. 3, no 10, e3308- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-20806DOI: 10.1371/journal.pone.0003308PubMedID: 18830411OAI: diva2:236163
Original Publication: Jana Sponarová, Sofia Nyström and Gunilla T Westermark, AA-amyloidosis can be transferred by peripheral blood monocytes, 2008, PloS one, (3), 10, e3308. Licensee: PLoS Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2009-10-30Bibliographically 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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1105
AA-amyloid, autophagy, resolution
National Category
Cell and Molecular Biology
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)
Available from: 2009-09-21 Created: 2009-09-02 Last updated: 2012-10-01Bibliographically approved

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