Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA.
Curr Alzheimer Res. 2010 Dec;7(8):656-64. doi: 10.2174/156720510793611592.
Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.
tau 是成熟神经元中主要的微管相关蛋白（MAP）。另外两种神经元 MAP 是 MAP1 和 MAP2。MAP 的一个既定功能是与微管结合并促进其组装成微管，以及稳定微管网络。磷酸化 tau 的微管组装促进活性受其磷酸化程度的调节。正常成人脑中的 tau 含有 2-3 摩尔磷酸盐/摩尔 tau 蛋白。tau 的过度磷酸化会抑制其生物活性。在阿尔茨海默病（AD）脑中，tau 的磷酸化程度比正常成人脑中的 tau 高出约三到四倍，并且在这种过度磷酸化状态下，它会聚合形成成对螺旋丝（PHF），与直丝（SF）混合形成神经原纤维缠结。在发育过程中和麻醉、低温期间，tau 会短暂过度磷酸化，但不会达到 AD 脑中的状态。AD 脑中异常过度磷酸化的 tau 与短暂过度磷酸化的 tau 不同，其区别在于（1）能够隔离正常 tau、MAP1 和 MAP2 并破坏微管，以及（2）自身组装成 PHF/SF。由于寡聚化，细胞质中异常过度磷酸化的 tau 与正常 tau 不同，可沉淀，并且在自我组装成 PHF/SF 时，失去隔离正常 MAPs 的能力。AD 脑中的一些 tau 被截断，这也促进了其自身组装。在额颞叶痴呆中发现的 tau 突变显然会促进其异常过度磷酸化。因此，AD 中异常过度磷酸化的 tau （1）与正常和短暂过度磷酸化的 tau 均可区分，并且（2）在细胞质/寡聚状态下具有抑制作用，但在自我组装成 PHF/SF 时没有抑制作用。抑制 tau 的异常过度磷酸化为 AD 和相关的 tau 病提供了一个有前途的治疗靶点。
