Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms
Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms
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DOI：
10.1111/j.1471-4159.2005.03270.x
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Wang, JZ
中科院分区：
文献类型：
--
作者：
Liu, R;Pei, JJ;Wang, JZ
微管相关蛋白tau的异常磷酸化在阿尔茨海默病(AD)以及受影响脑区能量代谢的显著降低中起着关键作用。为了探索急性能量危机对tau磷酸化的影响及其潜在机制，我们将大鼠脑片孵育在37℃的人工脑脊液(ACSF)中，或在有或没有氧气供应的ACSF中，或在低葡萄糖浓度的ACSF中。检测细胞总tau、磷酸化tau和非磷酸化tau的水平，以及蛋白磷酸酶(PP)-1、PP-2A、糖原合成酶-3(GSK-3)、细胞外信号调节蛋白激酶(ERK)和C-jun氨基末端激酶(JNK)的活性和水平。结果发现，在急性缺氧30min或120min时，tau在Ser396/Ser404(PHF-1)、Ser422(R145)、Ser199/Ser202(Tau-1)、Thr181(AT270)、Ser202/Thr205(AT8)和Thr231(AT180)上显著去磷酸化。PP-2A的活性和酪氨酸307(Tyr307)处去磷酸化的PP-2A催化亚基的水平同时增加。缺氧条件下ERK1/2和JNK1/2活性形式减少。PP-2A抑制剂冈田酸(OA，0.75mM)可完全阻止tau的急性缺氧去磷酸化，并使ERK1/2和JNK1/2的活性形式恢复到对照水平。急性缺氧时GSK-3和PP-1的活性和蛋白水平无明显变化。这些结果提示，急性缺氧诱导tau去磷酸化，PP-2A可能在急性缺氧诱导tau去磷酸化过程中起关键作用。
Abnormal phosphorylation of microtubule-associated protein tau plays a critical role in Alzheimer's disease (AD), together with a distinct decrease of energy metabolism in the affected brain regions. To explore the effect of acute energy crisis on tau phosphorylation and the underlying mechanisms, we incubated rat brain slices in artificial cerebrospinal fluid (aCSF) at 37 degrees C with or without an oxygen supply, or in aCSF with low glucose concentrations. Then, the levels of total, phosphorylated and unphosphorylated tau, as well as the activities and levels of protein phosphatase (PP)-1, PP-2A, glycogen synthase kinase 3 (GSK-3), extracellular signal-regulated protein kinase (ERK) and C-jun amino terminal kinase (JNK), were measured. It was found, unexpectedly, that tau was significantly dephosphorylated at Ser396/Ser404 (PHF-1), Ser422 (R145), Ser199/Ser202 (Tau-1), Thr181 (AT270), Ser202/Thr205 (AT8) and Thr231 (AT180) by acute anoxia for 30 min or 120 min. The activity of PP-2A and the level of dephosphorylated PP-2A catalytic subunit at tyrosine 307 (Tyr307) were simultaneously increased. The active forms of ERK1/2 and JNK1/2 were decreased under anoxic incubation. The PP-2A inhibitor, okadaic acid (OA, 0.75 mu m), completely prevented tau from acute anoxia-induced dephosphorylation and restored the active forms of ERK1/2 and JNK1/2 to the control level. The activities and protein levels of GSK-3 and PP-1 showed no change during acute anoxia. These data suggest that acute anoxia induces tau dephosphorylation, and that PP-2A may play a key role in tau dephosphorylation induced by acute anoxia.