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Lactadherin binds to elastin -a starting point for medin amyloid formation?
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
Vise andre og tillknytning
2006 (engelsk)Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 13, nr 2, s. 78-85Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Medin amyloid is found in the medial layer of the aorta in almost 100% of the Caucasian population over 50 years of age. The medin fragment is 5.5 kDa and derives from the C2-like domain of the precursor protein lactadherin. We have previously reported immunohistochemical findings showing that medin amyloid co-localizes with elastic fibers of arteries and herein we show that lactadherin also is associated with elastic structures of human aortic material. In addition, results from in vitro binding assays demonstrate that both medin and lactadherin bind to tropoelastin in a concentration-dependent fashion, suggesting that the lactadherin-tropoelastin interaction is mediated via the medin domain. It is possible that lactadherin, which is a cell adhesion protein, in this way connects smooth muscle cells to the elastic fibers of arteries. Given that both medin and lactadherin interact with elastic fibers, elastin is probably an important component in the formation of medin amyloid.

sted, utgiver, år, opplag, sider
2006. Vol. 13, nr 2, s. 78-85
Emneord [en]
amyloid, aorta, elastic fiber, elastin, medin, lactadherin, tropoelastin
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-11044DOI: 10.1080/13506120600722530ISI: 000240931800003PubMedID: 16911961OAI: oai:DiVA.org:uu-11044DiVA, id: diva2:38812
Tilgjengelig fra: 2008-01-29 Laget: 2008-01-29 Sist oppdatert: 2017-12-11bibliografisk kontrollert
Inngår i avhandling
1. Medin amyloid - a matter close to the heart: Studies on medin amyloid formation and involvement in aortic pathology
Åpne denne publikasjonen i ny fane eller vindu >>Medin amyloid - a matter close to the heart: Studies on medin amyloid formation and involvement in aortic pathology
2008 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Universitetsbiblioteket, 2008. s. 57
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 374
Emneord
AA amyloidosis, aging, amyloid, aneurysm, arterial media, dissection, elastin, medin amyloid, lactadherin, thoracic aorta
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-9275 (URN)978-91-554-7277-1 (ISBN)
Disputas
2008-10-10, Rudbecksalen, Rudbecklaboratoriet, C11, Dag Hammarköldsväg 20, Uppsala, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2008-09-18 Laget: 2008-09-18 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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