Abnormal phosphorylation of tan and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau
Abnormal phosphorylation of tan and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau
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DOI：
10.1073/pnas.94.1.298
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发表时间：
1997-01-07
影响因子：
11.1
通讯作者：
Iqbal, K
中科院分区：
文献类型：
--
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
微管相关蛋白（MAP）tau在阿尔茨海默病中异常过度磷酸化，并在经历神经元变性的神经元中积累。在本研究中，研究了阿尔茨海默病过度磷酸化tau蛋白（AD P-tau）与高分子量MAP（HMW-MAP）MAP 1和MAP 2的关系。发现AD P-tau在溶液中与MAP 1和MAP 2聚集。AD P-tau与MAP的结合导致MAP促进的微管组装的抑制。然而，与AD P-tau和正常tau的共聚集不同，AD P-tau和HMW-MAP之间的缔合不会导致细丝/缠结的形成。tau-AD P-tau结合的亲和力高于HMW-MAPs-AD P-tau结合的亲和力，因为正常tau抑制后者结合。AD P-tau和HMW-MAP之间的关联似乎也发生在原位，因为这些蛋白质从阿尔茨海默氏症脑提取物中共沉积，并且在沉积物中，HMW-MAP的水平与AD P-tau的水平相关。这些研究表明，异常磷酸化的tau可以螯合正常的tan和HMW-MAP并分解微管，但在生理条件下，只能从tau形成细丝缠结。
The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer disease and accumulates in neurons undergoing neurofibrillary degeneration. In the present study, the associations of the Alzheimer-hyperphosphorylated tau (AD P-tau) with the high molecular weight MAPs (HMW-MAPs) MAP1 and MAP2 were investigated. The AD P-tau was found to aggregate with MAP1 and MAP2 in solution. The association of AD P-tau to the MAPs resulted in inhibition of MAP-promoted microtubule assembly. However, unlike the coaggregation of AD P-tau and normal tau, the association between AD P-tau and the HMW-MAPs did not result in the formation of filaments/tangles. The affinity of the tau-AD P-tau association was higher than that of HMW-MAPs-AD P-tau because normal tau inhibited the latter binding. The association between AD P-tau and the HMW-MAPs also appeared to occur in situ because these proteins cosedimented from the Alzheimer brain extracts, and, in the sediment, the levels of the HMW-MAPs correlated with the levels of AD P-tau. These studies suggested that the abnormally phosphorylated tau can sequester both normal tan and HMW-MAPs and disassemble microtubules but, under physiological conditions, can form tangles of filaments only from tau.