Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor.
Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor.
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DOI：
10.1371/journal.pone.0002899
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发表时间：
2008-08-06
期刊：
影响因子：
3.7
通讯作者：
Cardoso I
中科院分区：
文献类型：
--
作者：
Costa R;Ferreira-da-Silva F;Saraiva MJ;Cardoso I
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是淀粉样β-肽（a - β）在大脑中沉积。转甲状腺素（TTR）是一种约55kda的四聚体蛋白，主要产生于肝脏和脑脉络膜丛。已知TTR的生理功能是通过与视黄醇结合蛋白结合，转运甲状腺激素T4和视黄醇。TTR也被证实是一种能够在体外切割apoa - 1的隐性蛋白酶。已经描述了TTR通过抑制和破坏a - β原纤维参与预防a - β纤原化，从而消除毒性。我们进一步表征了TTR/ a - β相互作用的性质，发现TTR，无论是重组的还是从人血清中分离出来的，都能够对a - β进行蛋白水解处理，通过质谱、反相色谱和n端测序确定，TTR能够在氨基酸残基1、2、3、10、13、14、16、19和27之后切割肽。通过硫黄素结合实验和透射电镜超微结构分析，a - β肽（1-14）和（15-42）的淀粉样蛋白形成潜力低于全长对应肽。当含有Kunitz蛋白酶抑制剂（KPI）结构域的αAPP肽存在时，TTR对a - β的切割受到抑制，但当不含KPI结构域的APP异构体695衍生的αAPP存在时，TTR对a - β的切割受到抑制。TTR还能降解a - β肽的聚集形式。我们的研究结果证实了TTR是AD的保护分子，并且TTR促进a - β蛋白水解是AD的保护机制。TTR可能被证明是一种有效的治疗药物，可以预防或延缓与AD病理有关的脑淀粉样斑块的形成。
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1–14) and (15–42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an αAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted αAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology.
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DOI：
10.1046/j.1432-1327.1999.00886.x
发表时间：
1999-12-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Caswell, MD;San Mok, S;Small, DH
通讯作者：
Small, DH
影响因子：
--
作者：
Lansbury, PT;Kosik, KS
通讯作者：
Kosik, KS
影响因子：
6.5
作者：
Liz, Marcia Almeida;Gomes, Claudio M.;Sousa, Monica Mendes
通讯作者：
Sousa, Monica Mendes
影响因子：
5.3
作者：
Choi, Se Hoon;Leight, Susan N.;Sisodia, Sangram S.
通讯作者：
Sisodia, Sangram S.
DOI：
10.1073/pnas.0712197105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Buxbaum, Joel N.;Ye, Zhengyi;Bartfai, Tamas
通讯作者：
Bartfai, Tamas