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Two different types of amyloid deposits-apolipoprotein A-IV and transthyretin-in a patient with systemic amyloidosis
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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2004 In: Laboratory Investigation, Vol. 84, 981-988 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 84, 981-988 p.
URN: urn:nbn:se:uu:diva-92105OAI: oai:DiVA.org:uu-92105DiVA: diva2:165064
Available from: 2004-09-10 Created: 2004-09-10Bibliographically approved
In thesis
1. Apolipoprotein A-IV and Transthyretin in Swedish Forms of Systemic Amyloidosis
Open this publication in new window or tab >>Apolipoprotein A-IV and Transthyretin in Swedish Forms of Systemic Amyloidosis
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils.

One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits.

In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR.

We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis.

We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 69 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1373
Pathology, Amyloid, Fibril, Aggregation, Apolipoprotein A-IV, Transthyretin, Seeding, Senile systemic amyloidosis, Familial amyloidotic polyneuropathy, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-4535 (URN)91-554-6032-1 (ISBN)
Public defence
2004-10-01, Rudbecksalen, Rudbecklaboratoriet, Rudbecklaboratoriet, Uppsala, 09:15
Available from: 2004-09-10 Created: 2004-09-10Bibliographically approved

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