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Signs of cross-seeding: aortic medin amyloid as a trigger for protein AA deposition
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
2011 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 18, no 4, 229-234 p.Article in journal (Refereed) Published
Abstract [en]

The highly diverse deposition pattern displayed by systemic amyloidoses, sometimes within the same amyloid disease, remains unexplained. The localized medin (AMed) amyloidosis develops from the precursor protein lactadherin and deposits in the media of the thoracic aorta in almost all individuals above 50 years of age. Given its high prevalence in the population, and the fact that systemic amyloidoses also deposit in the aorta, led us to investigate whether AMed amyloid could influence the tissue distribution of serum amyloid A derived (AA) amyloidosis. Seven aortas from patients with diagnosed systemic AA amyloidosis were investigated. Four displayed partial co-localization between medin and AA aggregates when examined with double-labeling immunofluorescence. Furthermore, in vitro studies showed that AMed amyloid-like fibrils promote the aggregation of protein AA into fibrils. The findings indicate that the highly frequent "senile" amyloidoses may have the potential to initiate fibril formation of the more uncommon amyloidoses by a cross-seeding mechanism.

Place, publisher, year, edition, pages
2011. Vol. 18, no 4, 229-234 p.
Keyword [en]
AA amyloid, AMed amyloid, aorta, cross-seeding, heterologous fibrils, medin, seed
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97525DOI: 10.3109/13506129.2011.630761ISI: 000296985200010OAI: oai:DiVA.org:uu-97525DiVA: diva2:172507
Available from: 2008-09-18 Created: 2008-09-18 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Medin amyloid - a matter close to the heart: Studies on medin amyloid formation and involvement in aortic pathology
Open this publication in new window or tab >>Medin amyloid - a matter close to the heart: Studies on medin amyloid formation and involvement in aortic pathology
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloidoses are a group of protein misfolding diseases characterized by deposits of insoluble fibrillar protein aggregates. Medin amyloid, which is the focus of this thesis, appears in the media of the thoracic aorta in nearly all individuals over 50 years. The fibrils are derived from a 50 amino acid residue fragment of the precursor protein lactadherin. How medin amyloid arises is unknown, but in paper I we demonstrated, with immunohistochemical and in vitro binding experiments, that both lactadherin and medin interact with elastin, implying that the elastic fibre is central in amyloid formation. In paper II, we further showed that the last 18-19 amino acid residues constitute the amyloid-promoting region.

In paper III, the consequence of medin deposition was investigated. Aortic specimens from patients with thoracic aorta aneurysm and dissection were examined for medin content. The tissue findings indicated that the two disease groups contained more medin oligomers than normal aortas. Interestingly, recent reports demonstrate that the toxicity of amyloid proteins is attributed to prefibrillar oligomeric aggregates rather than to mature fibrils. In support of this finding, we observed that prefibrillar medin, in contrast to medin fibrils, was toxic in cell culture.

Amyloid formation is a nucleation-dependent process. Addition of preformed fibrils to an amyloid protein solution dramatically accelerates fibrillation, a phenomenon called seeding. In paper IV, serum amyloid A-derived (AA) amyloid was found co-localized with medin deposits in the aorta. In vitro, medin fibrils enhanced the formation of AA fibrils, indicative of a seeding mechanism. The data are of great importance as they suggest that one type of amyloid is capable of inducing fibrillation and deposition of another amyloid type.

In conclusion, the results of this thesis shed light on how medin is formed, the function of lactadherin and the consequences of medin deposition for aortic pathology.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 374
Keyword
AA amyloidosis, aging, amyloid, aneurysm, arterial media, dissection, elastin, medin amyloid, lactadherin, thoracic aorta
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-9275 (URN)978-91-554-7277-1 (ISBN)
Public defence
2008-10-10, Rudbecksalen, Rudbecklaboratoriet, C11, Dag Hammarköldsväg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2008-09-18 Created: 2008-09-18 Last updated: 2009-05-18Bibliographically approved

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