Phosphorylated tau: toxic, protective, or none of the above.
Phosphorylated tau: toxic, protective, or none of the above.
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DOI：
10.3233/jad-2008-14404
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发表时间：
2008-08
期刊：
影响因子：
--
通讯作者：
Smith MA
中科院分区：
文献类型：
--
作者：
Castellani RJ;Nunomura A;Lee HG;Perry G;Smith MA
磷酸化tau蛋白作为神经元缠结（NFT）的主要蛋白组分的鉴定导致磷酸化tau蛋白具有固有毒性的概念，并且因此密切参与阿尔茨海默病（AD）发病机制。虽然表面上合乎逻辑，但这种构建忽略了AD中的许多关键发现，包括i）在存活神经元中遇到NFT直到晚期疾病; ii）NFT在神经元细胞质中持续数十年; iii）在认知完整的老年人中遇到NFT，有时数量可观;以及iv）具有NFT的神经元含有正常的微管内容物和结构。转基因动物模型的实验数据进一步证明，尽管tau蛋白受到抑制和行为正常化，NFT仍在神经元中积累。这些数据对磷酸化tau的固有毒性提出了质疑，似乎留下了特设“毒性中间体”磷酸化tau概念的唯一可行假设。然而，由于我们也知道磷酸化tau可以螯合氧化还原活性重金属并防止氧化应激，因此我们认为磷酸化tau具有对抗细胞毒性的保护作用。
Identification of phosphorylated tau as the major protein component of neurofibrillary tangles (NFTs) led to the concept that phosphorylated tau was inherently toxic and, as such, intimately involved in Alzheimer’s disease (AD) pathogenesis. While superficially logical, this construct ignores a number of key findings in AD, including i) that NFTs are encountered in viable neurons until late stage disease; ii) that NFTs persist within the neuronal cytoplasm for decades; iii) that NFTs are encountered, sometimes in significant numbers, in cognitively intact elderly; and iv) that neurons with NFTs contain normal content and structure of microtubules. Experimental data in transgenic animal models has further demonstrated that NFTs accumulate in neurons in spite of tau suppression and behavior normalization. These data call into question the inherent toxicity of phosphorylated tau, seemingly leaving the only viable hypothesis of the ad hoc “toxic intermediate” phosphorylated tau concept. However, since we also know that phosphorylated tau sequesters redox active heavy metals and protects against oxidative stress, here we suggest that phosphorylated tau serves a protective role against cellular toxicity.