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Review
. 2020 Nov 17;21(22):8672.
doi: 10.3390/ijms21228672.

Transthyretin Stabilization: An Emerging Strategy for the Treatment of Alzheimer's Disease?

Federica Saponaro  1 , Jin Hae Kim  2 , Grazia Chiellini  1
Affiliations
Review

Transthyretin Stabilization: An Emerging Strategy for the Treatment of Alzheimer's Disease?

Federica Saponaro et al. Int J Mol Sci. .

Abstract

Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in β-chains in a globular tetrameric protein, accounts for the predisposition of the protein to aggregate in fibrils, leading to a rare and severe disease, namely transthyretin amyloidosis (ATTR). Much effort has been made and still is required to find new therapeutic compounds that can stabilize TTR ("kinetic stabilization") and prevent the amyloid genetic process. Moreover, TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer's disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear. The aim of this review is to highlight the most relevant findings on the neuroprotective role of TTR, and to summarize the recent progress on the development of TTR tetramer stabilizers.

Keywords: Alzheimer’s disease; TTR stabilizers; amyloidosis; protein aggregation; protein misfolding; transthyretin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structural model of transthyretin (TTR) complexed with T4 (PDB 2rox). Upon forming a tetrameric complex, TTR constitutes two hydrophobic binding pockets, which are occupied by two T4 molecules in this model.
Figure 2
Figure 2
The proposed aggregation mechanism of transthyretin (TTR). The native tetrameric state of TTR [PDB 4tlt] is stable and physiologically active, while dissociation of non-native monomeric species [PDB 2nbo] initiates the pathogenic aggregation pathway of TTR. This results in accumulation of amyloid fibrils [PDB 6sdz].
See this image and copyright information in PMC

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