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The study of common cell death pathway between Altzheimer disease and ischemic neuronal cell death

阿尔茨海默病与缺血性神经细胞死亡共同细胞死亡途径的研究

基本信息

批准号：
17591519
负责人：
MORIOKA Motohiro
金额：
$ 1.98万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591519/
关键词：
brain ischemia Tau factor hyperphosphorylation Vanadate Apo-E リン酸化反応虚血性神経細胞死

项目摘要

We examined the sequential phsopharylational state of tau factor in CA1 delayed neuronal cell death (DND) after transient forebrain ischemia The hyperphosphorylation at serine 199/202 of tau factor was found in CAI neuronal cell 12hr to 1.5 days after transient ischemia, whereas serine 398 showed no obvious change. These hyperphosphrylation was not found in the CA1 obtained ischemia-torelance nor in CA3 neuron where neuronal cell death did not occur. These data suggested that hyperphorylation of tau 199/202 serine was related to neuronal cell death.Next, we examined which kinase played important role for tau hyperphosphrylation after ischemia We have injected several kinase inhibitor into animal lateral ventricle stereotactically after ischemia. According to inhibitor study, we concluded tha: cdk-5, Akt and GSK-3 kinases played important roles for tau hyperphosphorylation. Furthermore, calcineurin was suggested as an important phosphatase.We have prepared recombinat human tau by molecular biological technique; normal human tau-40, and dephosphorylated form human tau-40 (serine was changed to alanine at 199/202), both was conjugated to TAT-protein. We have injected both protein, which was expressed in E.Coli and purified, into lateral ventricle and these animals were subjected to ischemic insult. Only dephosphrylated form tau showed inhibitory effect for ischemic neuronal cell death (DND). The hyperphosphry lation of tau factor was considered as one of major causes of Altzheimer disease. Our data showed common cell death pathway between Altzheimer disease and ischemic neuronal cell death and novel therapeutic strategy for ischemic neurc nal cell death.We have reported vanadate have a protective effect for ischemic neuronal cell death. We examined the effect of vanadate for tau phosphorylation and obtained the data showed vanadate have an inhibitory effect against tau hyperphosphorylation.

我们观察了短暂性前脑缺血后CA 1区迟发性神经元细胞死亡（DND）中tau蛋白的顺序磷酸化状态。短暂性前脑缺血后12小时至1.5天，CA 1区神经元细胞tau蛋白丝氨酸199/202高度磷酸化，而丝氨酸398无明显变化。在缺血耐受的CA_1区和CA_3区神经元中均未发现这种高磷酸化。这些结果提示tau蛋白199/202丝氨酸的高磷酸化与神经细胞死亡有关。接下来，我们研究了缺血后哪些激酶在tau蛋白高磷酸化中起重要作用。通过抑制剂研究，我们认为：cdk-5、Akt和GSK-3激酶在tau蛋白过度磷酸化中起重要作用。我们利用分子生物学技术制备了重组人tau蛋白，正常人tau-40和脱磷酸化人tau-40（丝氨酸在199/202处变为丙氨酸）均与TAT蛋白偶联。我们将在大肠杆菌中表达并纯化的这两种蛋白注入侧脑室，使这些动物受到缺血性损伤。只有去磷酸化形式的tau蛋白显示出对缺血性神经元细胞死亡（DND）的抑制作用。Tau因子的高磷酸化被认为是阿尔茨海默病的主要病因之一。我们的数据显示了阿尔茨海默病和缺血性神经细胞死亡之间的共同细胞死亡途径以及缺血性神经细胞死亡的新治疗策略，我们已经报道了钒酸盐对缺血性神经细胞死亡具有保护作用。我们检测了钒酸盐对tau蛋白磷酸化的影响，并获得了钒酸盐对tau蛋白过度磷酸化具有抑制作用的数据。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CHOP is involved in neuronal apoptosis induced by neurotrophic factor deprivation

DOI：
10.1016/j.febslet.2006.05.021
发表时间：
2006-06-12
期刊：
FEBS LETTERS
影响因子：
3.5
作者：
Tajiri, Seiji;Yano, Shigetoshi;Gotoh, Tomomi
通讯作者：
Gotoh, Tomomi

Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischernia.

短暂前脑缺血后沙鼠海马 tau 因子丝氨酸 199/202 过度磷酸化。

DOI：
发表时间：
2006
期刊：
Biochem Biophys Res Commun. 347
影响因子：
0
作者：
Kai Y;Hamada J;Morioka M;Yano S;Mizuno T;Kuroda J;Todaka T;Takeshima H;Kuratsu J.;Morioka M. et al.
通讯作者：
Morioka M. et al.

Treatment of cavernous sinus dural arteriovenous fistulae by external manual carotid compression