Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis

Abstract

Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. “Amyloid seeds” are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.

Transthyretin cardiac amyloidosis

“…Notably, the addition of preformed seeds can significantly shorten or even complete this phase (seeding phenomenon). 13 Later, in the elongation phase, the addition of monomers to the nucleus results in formation of amyloid fibrils. These fibrils can be composed of a mixture of both C terminal fragments and full-length TTR (type A fibrils) or by full-length TTR only (type B fibrils).…”

Tissue Characterization in Cardiac Amyloidosis

“…The need for early diagnosis of CA and accurate amyloid typing is raising new problems and challenges for both physicians and pathologists [ 80 , 81 , 82 ]. The presence of a dual pathology, i.e., ATTR and AL amyloidosis developing subsequently in the same patient and affecting the heart, has been demonstrated in anecdotic cases, but the advancement in diagnostic tools will likely disclose more of these forms, which will then raise relevant issues for treatment strategies [ 15 , 56 , 83 ].…”

The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism

“…Many in vitro studies investigated the process leading to the metamorphosis of TTR from the globular (physiological) to the fibrils (pathological) structure [ 165 ]. All these studies focused on how TTR tetramers are modified, but the role of RBP or T4 in preserving TTR function in vivo was scarcely investigated.…”

“…Indeed, the ratio of wt-to-variant TTR shifted towards a greater contribution to the first [ 164 ]. This data suggested that remnant amyloid deposits of TTRv could represent a focal point for the deposition of the wild-type TTR (amyloid seeding) [ 165 ], furthermore showed that amyloid deposits underwent a turnover likely driven by dynamic processes of amyloid fibril formation and catabolism in the ECM.…”