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Amyloid deposits in transthyretin derived amyloidosis: Cleaved transthyretin is associated with distinct amyloid morphology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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2005 (English)In: The Internet Journal of Pathology, ISSN 1528-8307, Vol. 206, no 2, 224-232 p.Article in journal (Refereed) Published
Abstract [en]

The pathological fibrillar deposits found in the heart and other organs of patients with senile systemic amyloidosis (SSA) and Swedish familial amyloidotic polyneuropathy (FAP) contain wild-type (wt) and a mutant form of transthyretin (TTR), respectively. Previously, it was reported that these two forms of amyloid have different molecular features and it was thus postulated that the mechanism responsible for TTR fibrillogenesis in SSA and FAP may differ. To document further the nature of the amyloid in these entities, detailed morphological, histochemical, immunological, and structural analyses of specimens obtained from 14 individuals with SSA and 11 Swedish FAP patients have been performed. Two distinct patterns of amyloid deposition (designated A and B) were evident. In pattern A, found in all SSA and five of 11 FAP cases, the amyloid had a homogeneous but patchy distribution within the sub-endocardium, sub-epicardium, and myocardium; exhibited weak congophilia and green birefringence; and was composed of tightly packed, short, unorientated fibrils. This material contained mainly approximately 79-residue C-terminal fragments of the amyloidogenic precursor protein. In pattern B, seen in the six other FAP patients, the amyloid appeared as thin streaks throughout the cardiac tissue; often surrounded individual muscle cells; was strongly congophilic and birefringent; had long fibrils arranged in parallel bundles, often penetrating into myocytes; and was composed of virtually intact TTR molecules. These findings provide substantive evidence for the morphological and structural heterogeneity of TTR fibrils and suggest that the two types of deposition may reflect fundamental differences in the pathogenesis of the TTR-associated amyloidoses.

Place, publisher, year, edition, pages
2005. Vol. 206, no 2, 224-232 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92106DOI: 10.1002/path.1759PubMedID: 15810051OAI: oai:DiVA.org:uu-92106DiVA: diva2:165065
Available from: 2004-09-10 Created: 2004-09-10 Last updated: 2014-09-08Bibliographically 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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Bergström, JoakimWestermark, Per
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