Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity
Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity
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DOI：
10.1073/pnas.0712197105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Bartfai, Tamas
中科院分区：
文献类型：
--
作者：
Buxbaum, Joel N.;Ye, Zhengyi;Bartfai, Tamas
细胞已经进化到产生大量的分泌蛋白质，以服务于复杂的多细胞生物的综合功能，配备补偿蛋白质错误折叠。肝细胞和浆细胞具有发达的伴侣和蛋白酶体系统，以确保分泌的蛋白质有效地在细胞内转运。与蛋白质错误折叠相关的神经退行性疾病的数量表明，神经元对错误折叠分子聚集的致病作用特别敏感，因为这些系统在这一谱系中不太发达。淀粉样蛋白（A β(1-42)）肽的聚集在阿尔茨海默病（AD）的发病机制中起重要作用，尽管其确切机制尚不清楚。在研究蛋白质-蛋白质相互作用可能构成体内神经保护机制的遗传学研究中，在APP23转基因人AD小鼠模型中，过表达WT人转甲状腺素（TTR）转基因基因得到改善。内源性TTR基因的靶向沉默加速了神经病理表型的发展。在正常人和小鼠、AD患者和APP23小鼠的大脑中均可见到神经元内TTR。APP23脑显示细胞外TTR与斑块中的A β共定位。利用表面等离子体共振，我们在体外获得了TTR和A β聚集体之间直接蛋白-蛋白相互作用的证据。这些发现表明，TTR具有保护作用，因为它能够在细胞内和细胞外环境中以类似伴侣的方式结合有毒或毒性前的A β聚集体。这种相互作用可能代表了一种独特的正常宿主防御机制，增强这种机制可能在治疗上有用。
Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (A beta(1-42)) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with A beta in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and A beta aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic A beta aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.