Institute of Neuroimmunology, AD Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Curr Alzheimer Res. 2010 Dec;7(8):708-16. doi: 10.2174/156720510793611556.
Deposits of the misfolded neuronal protein tau are major hallmarks of neurodegeneration in Alzheimer's disease (AD) and other tauopathies. The etiology of the transformation process of the intrinsically disordered soluble protein tau into the insoluble misordered aggregate has attracted much attention. Tau undergoes multiple modifications in AD, most notably hyperphosphorylation and truncation. Hyperphosphorylation is widely regarded as the hottest candidate for the inducer of the neurofibrillary pathology. However, the true nature of the impetus that initiates the whole process in the human brains remains unknown. In AD, several site-specific tau cleavages were identified and became connected to the progression of the disease. In addition, western blot analyses of tau species in AD brains reveal multitudes of various truncated forms. In this review we summarize evidence showing that tau truncation alone is sufficient to induce the complete cascade of neurofibrillary pathology, including hyperphosphorylation and accumulation of misfolded insoluble forms of tau. Therefore, proteolytical abnormalities in the stressed neurons and production of aberrant tau cleavage products deserve closer attention and should be considered as early therapeutic targets for Alzheimer's disease.
在阿尔茨海默病（AD）和其他神经tau 病中，神经元蛋白 tau 的错误折叠沉积物是神经退行性变的主要标志。tau 从固有无序的可溶性蛋白转变为不溶的无序聚集的转化过程的病因引起了广泛关注。tau 在 AD 中经历了多种修饰，最显著的是过度磷酸化和截断。过度磷酸化被广泛认为是神经纤维病理的最热门诱导剂候选物。然而，在人类大脑中启动整个过程的真正动力仍然未知。在 AD 中，鉴定了几个特定部位的 tau 切割，并与疾病的进展相关。此外，AD 大脑中 tau 物种的 Western blot 分析显示出多种不同的截断形式。在这篇综述中，我们总结了证据表明，tau 的截断本身足以诱导神经纤维病理的完整级联反应，包括过度磷酸化和tau 的错误折叠不溶形式的积累。因此，应激神经元中的蛋白水解异常和异常 tau 切割产物的产生值得更密切关注，并应被视为治疗阿尔茨海默病的早期治疗靶点。
