title: Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology.
abstract: 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.
authors.affiliation: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Bergström
authors.forename: Asa
authors.initials: A
authors.lastname: Gustavsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Hellman
authors.forename: Knut
authors.initials: K
authors.lastname: Sletten
authors.forename: Charles L
authors.initials: CL
authors.lastname: Murphy
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Weiss
authors.forename: Alan
authors.initials: A
authors.lastname: Solomon
authors.forename: Bert-Ove
authors.initials: BO
authors.lastname: Olofsson
authors.forename: Per
authors.initials: P
authors.lastname: Westermark
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis* / Q000235:genetics / Q000648:ultrastructure; D028227:Amyloid Neuropathies, Familial / Q000378:metabolism / Q000473:pathology; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009206:Myocardium / Q000737:chemistry / Q000648:ultrastructure; D011228:Prealbumin / Q000378:metabolism*
chemical_list: D000682:Amyloid; D011228:Prealbumin