Amyloid is an in vivo fibrillar substance containing a fibril protein and several additional molecules. Presently, 25 proteins have been reported as main fibril components. Why just a few proteins form amyloid in vivo is still insufficiently understood. Many fibril proteins appear as fragments of larger precursors and for some types it is not clear whether fragmentation comes before or after fibrillation. The self-assembly by amyloid proteins can be speeded up by seeding with preformed fibrils. In mice, systemic amyloidoses are transmissible by a seeding mechanism. Whether this prion-like mechanism occurs in humans is not known, but can definitely not be ruled out.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2005.05024.x

Aspects on human amyloid forms and their fibril polypeptides.

Transthyretin (formerly called prealbumin) plays important physiological roles as a transporter of thyroxine and retinol-binding protein. X-ray structural studies have provided information on the active conformation of the protein and the site of binding of both ligands. Transthyretin is also one of the precursor proteins commonly found in amyloid deposits. Both wild-type and single-amino-acid-substituted variants have been identified in amyloid deposits, the variants being more amyloidogenic. Sequencing of the gene and the resulting production of a transgenic mouse model have resulted in progress toward solving the mechanism of amyloid formation and detecting the variant gene in individuals at risk.

Transthyretin: a review from a structural perspective.

Amyloid deposits in transthyretin-derived amyloidosis : cleaved transthyretin is associated with distinct amyloid morphology.

Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology.

Knowledge about the systemic amyloidoses has increased considerably during the last few years. This group of diseases is characterized by great biochemical variability, including at least 11 different amyloid fibril proteins and a remarkable range of clinical manifestations. With the understanding that the pathogenesis is different in the various forms of amyloidosis, it is now being increasingly accepted that an early and accurate diagnosis, including that of the underlying biochemical nature, is crucial for a successful treatment. The elucidation of the molecular mechanisms involved in amyloidogenesis is at the basis of the recent blossoming of new, innovative and more effective therapeutic approaches.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2796.2003.01262.x

The systemic amyloidoses: clearer understanding of the molecular mechanisms offers hope for more effective therapies.

Senile systemic amyloidosis (SSA) is a prevalent disease affecting the elderly and results from the pathologic deposition, predominantly in the heart, of unmutated (wild-type) transthyretin (TTR) molecules. This disorder differs from the familial TTR-associated amyloidoses that generally occur in a younger population and involves peripheral nerves but, notably, the deposits contain mutated (variant) forms of the amyloidogenic precursor protein. To gain further insight into the clinicopathologic features and pathogenesis of SSA, we have reviewed the post-mortem findings of 33 Swedish individuals (27 men, 6 women) who had pronounced cardiac amyloid disease. Additionally, in all cases there were amyloid deposits within the lungs. Seven of the patients were uremic, possibly due to fibrillar deposits in the renal medullary papilla. In contrast to other systemic amyloidoses, none of the 33 had more than minute congophilic material in the renal cortex, liver, or spleen. We have also analyzed the chemical composition of fibrils extracted from myocardium and have found that the protein consisted mainly of C-terminal fragments of TTR starting at positions 46, 49, and 52. Furthermore, we identified through antigenic mapping, an epitope present on the H strand of fibrillar, but not normal, plasma TTR molecules indicating that this strand is exposed in fibrils. We suggest that ATTR fibrils may develop both from full-length TTR and from C-terminal TTR fragments and that the N-terminal part is not necessary for the fibril integrity.

Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations.

Serum prealbumin and retinol-binding protein in the prealbumin-related senile and familial forms of systemic amyloidosis.

A prealbumin (PA)-like protein was demonstrated in amyloid fibrils both from a patient with senile systemic amyloidosis (SSA) and from a patient in northern Sweden with familial amyloidotic polyneuropathy (FAP). The investigated properties of this protein were similar in the two types of fibrils. The protein had molecular weight, antigenic determinants, and at least one cysteinyl residue in common with the subunit of normal PA. In contrast to normal PA, it contained disulphide-linked subunits and was to some extent bound to the fibril via the cysteinyl residues. The noncovalent forces between its subunits were weaker than in normal PA. It constituted part of the previously described AScl protein of the SSA fibrils. Proteins with lower molecular weight than the PA monomer were major proteins in both SSA and FAP fibrils. These proteins had similar properties in the two kinds of fibril and may be derived from PA. PA in serum from Swedish patients with FAP and SSA was normal with regard to the isoelectric pH of the monomers and tetramers.

Prealbumin in Swedish patients with senile systemic amyloidosis and familial amyloidotic polyneuropathy

Systemic amyloidosis was diagnosed in 150 patients by fine needle aspiration biopsy of subcutaneous abdominal fat tissue. The method has turned out to be rapid, safe and totally free of complication and is useful in all types of systemic amyloidosis. Subcutaneous abdominal fat tissue can also be used for typing of amyloid.

L. Benson

Papers

Serum prealbumin and retinol-binding protein in the prealbumin-related senile and familial forms of systemic amyloidosis.

Prealbumin in Swedish patients with senile systemic amyloidosis and familial amyloidotic polyneuropathy

Fine Needle Aspiration Biopsy of Abdominal Subcutaneous Fat Tissue for the Diagnosis and Typing of Amyloidosis