TAU HYPERPHOSPHORYLATION AFFECTS Smad 2/3 TRANSLOCATION
TAU HYPERPHOSPHORYLATION AFFECTS Smad 2/3 TRANSLOCATION
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DOI：
10.1016/j.neuroscience.2009.06.045
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发表时间：
2009-10-06
期刊：
影响因子：
3.3
通讯作者：
Love, S.
中科院分区：
文献类型：
--
作者：
Baig, S.;Van Helmond, Z.;Love, S.
转化生长因子β（TGF β）调节多种生物活性。Smad途径的TGF β激活导致编码细胞外基质分子、蛋白酶、蛋白酶激活剂和蛋白酶抑制剂的基因的激活。在阿尔茨海默病（AD）中，TGF β蛋白和mRNA水平升高，这将被预期是神经保护性的。然而，最近的观察表明，TGF β-Smad信号传导被tau的过度磷酸化破坏，tau是神经元缠结的主要成分：磷酸化的Smad 2/3（pSmad 2/3）与磷酸化的tau共同定位在神经元细胞质中，并且在细胞核中的水平降低。我们研究了体外诱导tau蛋白过度磷酸化是否会影响大鼠原代皮质细胞中pSmad 2/3的定位。用蛋白磷酸酶1和2A抑制剂冈田酸处理引起AD中过度磷酸化的表位处的tau过度磷酸化，并破坏pSmad 2/3易位到细胞核中。tau磷酸化对pSmad 2/3易位的破坏性作用通过用合成的寡聚体A β（1-42）（AD的更生理相关的模型）处理原代皮质细胞来证实。我们的研究结果表明，尽管AD中TGF β的水平增加，但由于过度磷酸化的tau蛋白对pSmad 2/3的隔离，TGF β-Smad信号通路在神经元内受到阻碍。这可能会损害TGF β的神经保护作用，并导致AD的神经退行性变。(C)2009年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Transforming growth factors beta (TGF beta) regulate multiple biological activities. TGF beta activation of the Smad pathway results in activation of genes encoding extracellular matrix molecules, proteases, protease activators and protease inhibitors. In Alzheimer's disease (AD), TGF beta protein and mRNA levels are raised, which would be expected to be neuroprotective. However, recent observations suggest that TGF beta-Smad signalling is disrupted by the hyperphosphorylation of tau, the primary component of neurofibrillary tangles: phosphorylated Smad2/3 (pSmad 2/3) co-localises with phosphorylated tau in the neuronal cytoplasm and levels are reduced in the nucleus. We have investigated whether in vitro induction of tau hyperphosphorylation influences pSmad 2/3 localisation in rat primary cortical cells. Treatment with okadaic acid, a protein phosphatase 1 and 2A inhibitor caused hyperphosphorylation of tau at epitopes hyperphosphorylated in AD and disrupted pSmad 2/3 translocation into the nucleus. The disruptive effect of tau phosphorylation on pSmad 2/3 translocation was confirmed by treatment of primary cortical cells with synthetic oligomeric A beta(1-42), a more physiologically relevant model of AD. Our findings suggest that despite the increased level of TGF beta in AD, the TGF beta-Smad signalling pathway is impeded within neurones due to sequestration of pSmad 2/3 by hyperphosphorylated tau. This may compromise neuroprotective actions of TGF beta and contribute to neurodegeneration in AD. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.