Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia
Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia
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DOI：
10.1016/j.bbrc.2006.06.096
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发表时间：
2006-08-18
影响因子：
3.1
通讯作者：
Kuratsu, Jun-ichi
中科院分区：
文献类型：
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作者：
Morioka, Motohiro;Kawano, Takayuki;Kuratsu, Jun-ichi
我们研究了短暂前脑缺血后海马迟发性神经元死亡（DND）中tau蛋白的磷酸化状态。短暂性缺血后，明显观察到tau因子丝氨酸199/202而非丝氨酸396的短暂磷酸化增加。脑室内注射奥洛莫辛和U-0126（分别为CDK 5和MAP激酶抑制剂）抑制过度磷酸化。相反，渥曼青霉素（PI 3激酶抑制剂）增加丝氨酸199/202的磷酸化，并与GSK 3磷酸化的增加相对应。我们的研究结果表明，CDK 5，MAP激酶，和GSK 3磷酸化这些网站缺血后。我们用TAT-HA蛋白制备了重组正常人Tau（N-Tau 40）和去磷酸化形式的人Tau-40（D-Tau 40），其中199/202个丝氨酸通过定点突变变成了丙氨酸。脑室注射D-tau 40对DND有一定的保护作用，而N-Tau 40则无此作用。这些数据表明，tau因子的丝氨酸199/202处的过度磷酸化由MAP激酶CDK 5诱导。和GSK 3，并有助于缺血性神经元损伤。(c)2006年爱思唯尔公司All rights reserved.
We examined the phosphorylation state of tau factor in hippocampal delayed neuronal death (DND) after transient forebrain ischemia. A transient phosphorylation increase at serine 199/202 but not serine 396 of tau factor after transient ischemia was clearly observed. Intraventricular injections of olomoucine and U-0126 (CDK5 and MAP kinase inhibitors, respectively) inhibited hyperphosphorylation. In contrast, wortmannin (PI3 kinase inhibitor) increased phosphorylation at serine 199/202 and corresponded with an increase in GSK3 phosphorylation. Our findings suggest that CDK5, MAP kinase, and GSK3 phosphorylate these sites after ischemia. We prepared recombinant normal human tau (N-Tau40) with TAT-HA protein and dephosphorylated-form human Tau-40 (D-tau40) in which 199/202 serines were changed to alanine by site-directed mutagenesis. Intraventricularly injected D-tau40 protected somewhat against DND while N-Tau40 did not. These data suggest that hyperphosphorylation at serine 199/202 of tau factor is induced by MAP kinase, CDK5. and GSK3, and contributes to ischemic neuronal injury. (c) 2006 Elsevier Inc. All rights reserved.