Unravelling the myriad physiologic roles of transthyretin: critical considerations for treating transthyretin amyloidosis

Abstract

Background: Transthyretin (TTR) is a highly conserved protein with crucial and broadly protective physiologic roles across organ systems and diseases. Evidence shows that TTR contributes to neuroprotection, cognition, glucose regulation, pregnancy, muscle development, and bone mineralization. In several disease states, including diabetes, Alzheimer's disease, Lewy body dementia, cerebrovascular disease, and osteoporosis, higher TTR levels may be protective. Numerous studies have shown that low levels of TTR are associated with increased mortality overall and in relation to cardiovascular disease and several malignancies.

Purpose: There is a growing portfolio of approved and investigational transthyretin amyloidosis (ATTR) treatments that differ in their mechanisms and effects on circulating TTR. When selecting an ATTR therapy, clinicians must decide whether to stabilize and preserve TTR and its functions or knockdown and drastically reduce TTR. This review summarizes the vital physiologic roles of TTR in health and disease. We consider the potential effects on normal biologic pathways that may occur while therapeutically suppressing TTR and discuss clinical decisions concerning ATTR therapies in the context of the summarized literature.

Discussion: TTR is essential for a broad range of physiologic processes and may confer clinically protective effects in neurologic and other organ systems. While a link between low TTR and severe disease and mortality is well established, it remains unclear whether long-term TTR suppression via ATTR therapies increases risk of disease. Clinical decisions in ATTR, however, should reflect the current understanding of the roles of TTR and the patient's clinical history.

Conclusion: TTR serves vital physiologic roles across organ systems. Given its clinically protective properties, continued investigation into the potential long-term impact of TTR suppression via knockdown or gene editing therapies is prudent. ATTR treatment selection should reflect an awareness of the physiologic importance of TTR, as well as consideration of the potential long-term impact of chronic TTR suppression.

Keywords: ATTR; Alzheimer’s disease; TTR; Transthyretin; amyloidosis; cardiovascular disease; cerebrovascular disease; genetics; neurodegenerative disorders; prealbumin.

Figure 1.

The putative role of TTR in health and disease. Evidence from animal models has shown an effect of TTR on maintaining ‘normal’ memory, with the absence of TTR impairing spatial learning and accelerating cognitive decline typically associated with aging [35–38]; TTR also promoted neuritogenic activity in the central and peripheral nervous systems in animal studies in vitro and in vivo [39–42]. TTR may have neuroprotective activities in Alzheimer’s disease, Parkinson’s disease, and TDP-43-associated neuropathies by binding, degrading, and/or clearing harmful protein aggregates [43–47]. TTR has been implicated in cardiovascular health in epidemiological studies [9,48,49]. Regulation of TTR expression appears to be essential for the maintenance of healthy pregnancy and normal fetal development in mice [50,51]. Lower levels of TTR have been linked to higher mortality in the general elderly population, as well as several oncological diseases, respiratory diseases, cardiovascular diseases, and ATTR [9,52–57]. In ex vivo pancreatic islet preparations, TTR had a role in glucose-induced insulin release and offered protection against β-cell apoptosis [58]. In in vitro animal models, TTR appeared to participate in the development and regeneration of muscle cells [59,60]. Destabilized forms of TTR distorted the morphology of calcium carbonate crystals in vitro, suggesting the involvement of TTR in healthy bone mineralization [61]. ATTR, transthyretin amyloidosis; TDP-43, trans-activation response DNA-binding protein 43 kDa; TTR, transthyretin.

Figure 2.

Role of TTR in Alzheimer’s disease. TTR has proteolytic activity capable of cleaving Aβ monomers and oligomers, potentially contributing to their clearance [46]. In vitro results from a mouse model of Alzheimer’s disease showed that TTR tetramers bind Aβ monomers, preventing Aβ oligomerization [46]. Results from laboratory assays indicated that TTR monomers bind Aβ oligomers, inhibiting their polymerization to fibrils [95]. Tetrameric TTR increased transmembrane LRP1 levels, potentially contributing to clearance of Aβ from the brain [43,94]. BBB dysfunction, which is characteristic of Alzheimer’s disease, results in increased in vascular permeability [84,85]; it would be interesting to determine whether this increased permeability extends to the ability of ATTR therapies to cross the BBB. Aβ, amyloid beta; ATTR, transthyretin amyloidosis; BBB, blood–brain barrier; LRP1, low-density lipoprotein receptor-related protein 1; TTR, transthyretin.

Figure 3.

Role of TTR in type 1 diabetes. In cultures of human retinal microvascular endothelial cells, TTR mitigated the damaging cell proliferation, migration, and angiogenesis effects of high glucose concentration by inhibiting the VEGFA/PI3K/AKT pathway [136]. In mice, TTR insufficiency caused elevated plasma glucose concentration, decreased expression of influx glucose transporters GLUT1, GLUT3, and GLUT4, increased expression of efflux glucose transporter GLUT2, reduced levels of the glycolytic enzyme pyruvate kinase M, and impaired mitochondrial activity [63]. In ex vivo pancreatic islet preparations, the TTR tetramer had a role in glucose-induced insulin release by enhancing the depolarization of the voltage-gated Ca²⁺ channel, and offered protection against apolipoprotein CIII-induced β-cell apoptosis [58]. In contrast, the TTR monomer did not affect glucose-induced insulin release or apolipoprotein CIII-induced β-cell apoptosis [58]. TTR, transthyretin.