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Deposition and Resolution of AA Amyloid
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. (Westermark GT, Amyloidgruppern)
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 [en]
AA-amyloid, autophagy, resolution
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-20292ISBN: 978-91-7393-684-2 (print)OAI: oai:DiVA.org:liu-20292DiVA: diva2:233835
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
List of papers
1. 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: 2017-12-13Bibliographically approved
2. AA-amyloidosis can be transferred by peripheral blood monocytes
Open this publication in new window or tab >>AA-amyloidosis can be transferred by peripheral blood monocytes
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20806 (URN)10.1371/journal.pone.0003308 (DOI)18830411 (PubMedID)
Note
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. http://dx.doi.org/10.1371/journal.pone.0003308 Licensee: PLoS Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2009-10-30Bibliographically approved
3. AA-Amyloid is cleared by endogenous immunological mechanisms
Open this publication in new window or tab >>AA-Amyloid is cleared by endogenous immunological mechanisms
2012 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, no 3, 138-145 p.Article in journal (Refereed) Published
Abstract [en]

Reactive amyloidosis is a complication to longstanding inflammatory diseases.Protein amyloid A (AA), an N-terminal fragment of the acute phase protein serumamyloid A, undergoes conformational changes and is deposited as amyloid in tissue.AA-amyloidosis is reversible and reduction of amyloid mass has been reported as theinflammation ceases. Not much is known about the endogenous factors thatcontribute to amyloid resolution. Herein, we describe the dynamics of amyloiddegradation in experimental murine AA-amyloidosis and show that amyloiddegradation depends on macrophages and antibody formation. AA-amyloidosis wasinduced in mice and resolution of amyloid was monitored over time by histologicaltechniques. Internalized amyloid was present in macrophages that appeared at siteof deposition. At 9 months, when virtually all amyloid was cleared, amyloidosis wasre-induced in one group of animals by a single silver nitrate injection. This causedeposition of excessive amounts of amyloid, and indicate that even thoughundetectable the amyloid reseed in the body and can there act as amyloid enhancingfactor. Antibodies directed against protein AA were detected in animals duringamyloid clearance by ELISA-technique. Passive immunization with an amyloidspecific monoclonal antibody, produced by a B-cell clone recovered from an animalwith advanced AA-amyloidosis, diminish amyloid deposits in murine AA-amyloidosis.Immunoglobulins co-localize with amyloid deposits and can contribute to amyloiddegradation by Fc-receptor mediated phagocytosis.

Keyword
Amyloid A (AA), Amyloid β(Aβ), Amyloid light chain (AL), Alzheimer’s disease (AD), amyloid enhancing factor (AEF), serum amyloid A (SAA), tumour necrosis factor (TNF)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20807 (URN)10.3109/13506129.2012.711391 (DOI)000307635600004 ()
Note

funding agencies|Swedish Research Council|2010-55x-20326-04-3|Swedish Rheumatology Association||

Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
4. Cardiac Amyloid in Experimental AA Amyloidosis is Associated with IncreasedAutophagic Activity
Open this publication in new window or tab >>Cardiac Amyloid in Experimental AA Amyloidosis is Associated with IncreasedAutophagic Activity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Cardiac involvement in reactive amyloidosis is a severe complication that leads to reducedsurvival. We induced reactive amyloidosis in mice by induction of chronic inflammation andfound that cardiac involvement develops later than spleen and liver deposits. TEM studiesrevealed intracellular amyloid deposits, but endogenous production of SAA1, SAA2 or SAA3by the cardiomyocytes was not supported by mRNA analysis. Therefore, the intracellulardeposits of protein AA must derive from SAA produced at another location. Autophagosomeswere present in close association with intracellular amyloid and the autophagy marker LC3was increased 20 times in cardiac tissue with moderate amounts of amyloid. Increase in LC3was not paralleled by an increase in LAMP-2. The ER-stress marker Bip was unchanged ininflamed heart tissue and in amyloid-containing heart. Even though procaspase-12 increasedin heart after silver nitrate injections and in heart with AA-amyloid, no active caspase-12could be detected. We suggest that autophagosomes are involved in amyloid clearance, buttheir accumulation indicate that the formation of autophagolysosomes is hampered.

Keyword
AA-amyloid, cardiomyocytes, autophagy, Amyloid enhancing factor (AEF)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20808 (URN)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2010-01-14Bibliographically approved

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