It is becoming clear that transthyretin amyloid accumulation makes a meaningful contribution to cardiovascular disease and a range of other conditions over the course of normal aging. It remains poorly explored, but that will likely change in the years ahead now that there are treatments capable of reducing the amount of transthyretin amyloid in the body. Clinical development of these therapies is initially focused on the rare cases of transthyretin amyloidosis in which inherited mutations greatly speed the process of amyloid formation, but some of them appear to also work for the amyloids that form in normally aged individuals. The ability to remove transthyretin amyloid in humans is all still quite new as of recent years, however, and progress is always very slow in the research and medical communities.
The native tetrameric form of transthryetin (TTR) is a protective factor against oxidative stress. TTR is involved in reactive oxygen species (ROS) balance, extracellular matrix (ECM) remodeling, autophagy, apoptosis, reverse HDL cholesterol transport, proliferation, and angiogenesis under physiological conditions and in pathological disorders or stress-induced insults. The formation of TTR amyloid is induced by oxidative modification, aging, mutation, metal ions (including Ca2+), plasmin, and negatively charged polymers. The factors that compromise structural stability and lead to amyloid formation upon dysregulation may be responsible for improper/mislocated induction of TTR and result in cytotoxic TTR amyloid.
The contribution of TTR to cardiovascular and osteoarticular diseases is associated with the formation of TTR amyloid and calcification in the vascular and ligament tissues. Low levels of TTR in the plasma are observed in CVDs and the majority of osteoarticular disorders. It is difficult to determine whether changes in the processes or TTR levels correspond to a cause or a consequence of amyloid formation and whether adverse effects observed in amyloid-induced diseases are a consequence of amyloid overload or a loss of the protective functions of TTR.
Unaggregated/native and aggregated/amyloid TTR forms are interconnected in the following loops. Vicious cycle 1, oxidative stress: oxidative modifications lead to TTR destabilization and pathological amyloid, which increases oxidative stress. Properly folded TTR is a factor that suppresses oxidative stress, inhibits intracellular Ca2+ influx, ROS production, membrane permeabilization, apoptosis, and autophagy, and promotes the assembly of oligomeric proteins into larger, less toxic aggregates. Vicious cycle 2, Ca2+: TTR amyloid is formed in situ in response to high Ca2+ concentration, which, in turn, promotes TTR destabilization and amyloid deposition, which entraps more Ca2+. Vicious cycle 3, inflammation: plasmin or other factors induce the formation of TTR amyloid. Amyloid deposits cause plasmin activation and induce inflammation, which, in turn, promotes amyloid formation. Vicious cycle 4, lipids: cholesterol and anionic phospholipids bind TTR and promote TTR aggregation. On the other hand, aggregated TTR alters membrane fluidity and induces cytotoxic effects, upregulating TTR aggregation.