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The Importance of Macrophages, Lipid Membranes and Seeding in Experimental AA Amyloidosis
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloidosis is a group of protein misfolding diseases caused by tissue deposition of fibrillary protein aggregates termed amyloid. Amyloid A (AA) amyloidosis is a systemic form of amyloidosis that occurs as a complication of chronic inflammatory diseases, such as rheumatoid arthritis, familial Mediterranean fever and chronic infections, such as tuberculosis. AA amyloid is derived from the precursor protein serum amyloid A and is deposited in several organs preferably kidneys, liver and spleen. AA amyloidosis can be induced in mice by long standing inflammatory stimulation and concurrent administration of tissue extracts of AA amyloid, referred to as amyloid enhancing factor (AEF), reduces the time for amyloid deposition in the marginal zone of the spleen from 5 weeks to 2 days. The general aim of this thesis was to investigate the mechanisms involved in the development of AA amyloid in the mouse model of AA amyloidosis.

Amyloid was induced in inflamed mice by injection of AEF and amyloid toxicity to splenic macrophages was investigated. We found that the marginal zone macrophages were very sensitive to amyloid formation and increasing amyloid load caused progressive depletion of these cells, whereas red pulp macrophages and metallophilic marginal zone macrophages appeared unaffected. To clarify the role of splenic macrophages in amyloidogenesis, macrophages were depleted by clodronate containing liposomes. We displayed that in the absence of splenic macrophages, especially marginal zone macrophages, amyloid formation was delayed implying a crucial role of macrophages in amyloid formation.

The effect of lipid membranes on amyloid formation was studied and we showed that liposomes exhibited an amyloidogenic effect in inflamed mice although not as powerful as AEF. Following the fate of the liposomes, we showed that liposomes were rapidly cleared by uptake in the spleen and liver and colocalized with lysosomes. A tentative mechanism might be that accumulation of liposomes in lysosomes interfere with the SAA degradation process facilitating amyloid formation.

Finally the conformational properties of two AEF (AEF1 and AEF2) preparations were studied using conformation sensitive luminescent-conjugated oligothiophenes (LCOs). We found that AEF1 and AEF2 displayed significantly different ultrastructure as well as conformation and consequently induced different cytotoxicity in vitro. Inducing amyloid formation in inflamed mice by AEF1 and AEF2 revealed that the polymorph of the amyloid aggregates was replicated in vivo.

In summary, the results obtained in this thesis indicate an important role for macrophages for the formation of amyloid. The existence of amyloid strains has long been an in vitro finding, but the finding that AEF ultrastructure drives the morphology of newly formed amyloid in vivo opens up for new studies that can help us to understand the formation of homologous and heterologous fibrils. Thus, the fundamental mechanisms of various amyloid diseases are similar and the results presented in the thesis can increase the understanding of other amyloid diseases.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 60
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1687
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-159658DOI: 10.3384/diss.diva-159658ISBN: 9789176850503 (print)OAI: oai:DiVA.org:liu-159658DiVA, id: diva2:1343021
Public defence
2019-09-12, Berzeliussalen, Hus 463, Hälsouniversitetet, Linköping, 09:00 (English)
Opponent
Supervisors
Note

Incorrect affiliation to Division of Experimental Pathology in publication. Correct affiliation is Division of Cell Biology.

Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2019-08-16Bibliographically approved
List of papers
1. Depletion of Spleen Macrophages Delays AA Amyloid Development: A Study Performed in the Rapid Mouse Model of AA Amyloidosis
Open this publication in new window or tab >>Depletion of Spleen Macrophages Delays AA Amyloid Development: A Study Performed in the Rapid Mouse Model of AA Amyloidosis
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e79104-Article in journal (Refereed) Published
Abstract [en]

AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM), marginal zone macrophages (MZM), metallophilic marginal zone macrophages (MMZM). MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.

Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102982 (URN)10.1371/journal.pone.0079104 (DOI)000327254700092 ()
Note

Funding Agencies|Swedish Research Council|GTW5343|County Council of Ostergotland Magnus Bergvalls research foundation||Ingrid Svenssons research foundation||Broderna Karlssons research foundation||Hildur Pettersons research foundation||

Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2019-08-15
2. Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis
Open this publication in new window or tab >>Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis
Show others...
2019 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no 1, p. 34-44Article in journal (Refereed) Published
Abstract [en]

Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

Methods: Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.

Results: We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.

Conclusions: We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Amyloid; liposomes; lipid membrane; macrophages; AA amyloidosis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-157278 (URN)10.1080/13506129.2019.1576606 (DOI)000466218300001 ()30929476 (PubMedID)2-s2.0-85063746690 (Scopus ID)
Note

Funding Agencies|County Council of Ostergotland; Magnus Bergvalls Research Foundation; Broderna Karlssons Research Foundation; K. Molins Minnesfond and Hildur Pettersons Research Foundation

Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-08-15Bibliographically approved

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