The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System
The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System
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DOI：
10.1016/j.ajpath.2012.06.033
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发表时间：
2012-10-01
影响因子：
6
通讯作者：
Hyman, Bradley T.
中科院分区：
文献类型：
--
作者：
Tai, Hwan-Ching;Serrano-Pozo, Alberto;Hyman, Bradley T.
在阿尔茨海默病（AD）中，新皮层和边缘系统中神经元缠结的沉积和突触的丧失各自与认知损害强烈相关。缠结由错误折叠的过度磷酸化的tau蛋白组成;然而，tau异常和突触功能障碍之间的联系仍不清楚。我们使用生化和形态学方法研究了tau蛋白在对照和AD皮质中的位置。我们发现，除了其良好的轴突定位，正常的tau蛋白是目前在突触前和突触后终端在控制人类大脑。在AD中，tau在突触前和突触后末端变得过度磷酸化和错误折叠，并且这种异常的突触后修饰的tau在突触神经体组分中富集。突触tau蛋白似乎是过度磷酸化和泛素化的，并形成稳定的寡聚体抵抗SDS变性。过度磷酸化的tau寡聚体在人AD突触处的积累与增加的泛素化底物和增加的蛋白酶体组分相关，这与泛素-蛋白酶体系统的功能障碍一致。我们的研究结果表明，突触过度磷酸化的tau寡聚体可能是破坏AD突触的蛋白毒性的重要介质。(Am J Pathol 2012，181：1426-1435; http：//dx·doi·org/10·1016/j·ajpath·2012·06·033）
In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD. (Am J Pathol 2012, 181:1426-1435; http://dx.doi.org/10.1016/j.ajpath.2012.06.033)