Department of Pathology, University of Pisa, 56100 Pisa, Italy.
Department of New Biology, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu 42988, Korea.
Int J Mol Sci. 2020 Nov 17;21(22):8672. doi: 10.3390/ijms21228672.
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.
转甲状腺素蛋白（TTR），以前称为前白蛋白，是一种主要由肝脏和脉络丛（CP）分泌的血浆蛋白，是甲状腺激素（THs）和视黄醇（维生素 A）的载体。TTR 的结构，由四个富含β-链的单体组成，形成一个球状四聚体蛋白，这使得该蛋白容易在原纤维中聚集，导致一种罕见且严重的疾病，即转甲状腺素淀粉样变性（ATTR）。人们已经并将继续努力寻找新的治疗化合物，这些化合物可以稳定 TTR（“动力学稳定”）并阻止淀粉样形成过程。此外，由于 TTR 在认知障碍和阿尔茨海默病（AD）等背景下具有公认的神经保护特性，因此它是神经退行性疾病的一个有趣的治疗靶点。大量证据已经收集到了 TTR 在 AD 中的神经保护作用，包括通过体外和体内研究以及广泛的临床系列。尽管 TTR 的神经保护作用得到了支持，但机制仍不完全清楚。本文旨在强调 TTR 神经保护作用的最相关发现，并总结 TTR 四聚体稳定剂开发的最新进展。
