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The role of presenilin in the formation of neurofibrillary tangles via GSK-3β

早老素通过 GSK-3β 在神经原纤维缠结形成中的作用

基本信息

批准号：
15590879
负责人：
IKEDA Masaki
金额：
$ 1.92万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590879/
关键词：
FTDP-17 tauopathy GSK-3beta トランスジェニックマウスタウ GSK3β

项目摘要

We generated the transgenic mice overexpressing GSK-3β cDNA ligating mouse Thy-1 promoter, in order to elucidate the relationship of the interaction GSK-3β and tau accumulation. We examined the immunocytochemistry of the brains slides of 3,6,12-month-old transgenic mice. Glycogen synthase kinase-3β(GSK-3β) plays an important role in phosphorylation of tau. This evidence is thought to be induced to form neurofibrillary tangles(NFT) observed in tauopathies including Alzheimer's disease. It is crucial to elucidate the mechanism of GSK-3β involved in NFT and neuronal cell death, to develop novel therapy for these diseases. To elucidate immunocytochemical changes of cytoskeltal structures in GSK-3β transgenic mice. To examine immunocytochemical study of three GSK-3β transgenic mice brains and spinal cords at 3,8 and 12 months. We examined immunocytochemical study of transgenic mice overexpressing a constitutively active GSK-3β(S9A), and demonstrate that the expression of GSK-3β increased in the cytoplasm and dendrites of neuronal cells in age dependent manner at 3 to 12 months. The reduction of the level of the microtubule-associated protein 2(MAP2) in brain and in spinal cord, and immunoreactivity of neurofilament by antibodies SMI-31,NF-200 slightly decreased in the dendrites of neurons. These findings suggested that overexpression of GSK-3β in vivo led to decrease of phophorylated neurofilaments and MAP2 protein in neuronal cells, leading to aberrant change of cytoskeltal structures and neuronal dysfuction.

我们构建了过表达GSK-3β cDNA并连接小鼠Thy-1启动子的转基因小鼠，以阐明GSK-3β与tau积累相互作用的关系。我们检查了 3、6、12 个月大转基因小鼠脑部切片的免疫细胞化学。糖原合成酶激酶-3β(GSK-3β) 在 tau 磷酸化中发挥重要作用。这一证据被认为是在包括阿尔茨海默氏病在内的 tau蛋白病中观察到的，被诱导形成神经原纤维缠结 (NFT)。阐明 GSK-3β 参与 NFT 和神经元细胞死亡的机制对于开发这些疾病的新疗法至关重要。阐明 GSK-3β 转基因小鼠细胞骨架结构的免疫细胞化学变化。检查三只 GSK-3β 转基因小鼠 3、8 和 12 个月时大脑和脊髓的免疫细胞化学研究。我们对过表达组成型活性 GSK-3β(S9A) 的转基因小鼠进行了免疫细胞化学研究，并证明 GSK-3β 的表达在 3 至 12 个月时以年龄依赖性方式在神经元细胞的细胞质和树突中增加。脑和脊髓中微管相关蛋白2（MAP2）水平降低，神经元树突中抗体SMI-31、NF-200对神经丝的免疫反应性略有降低。这些发现表明，体内GSK-3β的过度表达导致神经元细胞中磷酸化神经丝和MAP2蛋白的减少，导致细胞骨架结构的异常变化和神经元功能障碍。