Analysis of functional roles of presenilin and GSK-3β in molecular mechanism of neurofibrillary tangles

早老素和GSK-3β在神经原纤维缠结分子机制中的功能分析

• 批准号: 17590860
• 负责人: IKEDA Masaki
• 金额: $ 2.24万
• 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: 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-17590860/
• 关键词: tauopathy; Dementia; Alzheimer's disease; FTDP-17; neurofibrillary tangle; プレセニリン; アルツハイマー病; タウオパチー; GSK-3β; ミスセンス変異; タウ

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 and Western blot of GSK-3β transgenic mice brains 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 dysfunction.

糖原合成酶激酶-3β(GSK-3β)在tau蛋白的磷酸化中起重要作用。这种证据被认为是诱导形成神经原纤维缠结（NFT），在包括阿尔茨海默病在内的tau病中观察到。阐明GSK-3β参与NFT和神经元细胞死亡的机制，对开发新的治疗方法具有重要意义。目的：探讨GSK-3β转基因小鼠细胞骨架结构的免疫细胞化学变化。目的：观察GSK-3β转基因小鼠3、8、12月龄脑组织免疫细胞化学和Western blot的变化。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，发现GSK-3β在神经元细胞的细胞质和树突中的表达在3 ~ 12月龄时呈年龄依赖性增加。SMI-31、NF-200抗体可使脑和脊髓内微管相关蛋白2 （MAP2）水平降低，神经元树突内神经丝的免疫反应性略有下降。上述结果提示，GSK-3β在体内的过度表达可导致神经元细胞中磷酸化的神经丝和MAP2蛋白的减少，导致细胞骨架结构的异常改变和神经元功能障碍。

项目成果

Cortical neuronal and glial pathology in TgTauP301L transgenic mice -: Neuronal degeneration, memory disturbance, and phenotypic variation

• DOI: 10.2353/ajpath.2006.051250
• 发表时间: 2006-10-01
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Murakami, Tetsuro;Paitel, Erwan;Shoji, Mikio
• 通讯作者: Shoji, Mikio

Enhanced accumulation of tau in doubly transgenic mice expressing mutant betaAPP and presenilin-1.

表达突变型 betaAPP 和早老素-1 的双转基因小鼠中 tau 蛋白的积累增强。

• 发表时间: 2006
• 期刊: Brain Research 1094(1)
• 作者: Samura E;Kawarabayashi T;Ikeda M;et al.
• 通讯作者: et al.

Enhanced accumulation of tau in doubly transgenic mice expressing mutant betaAPP and presenilin-l

表达突变型 betaAPP 和早老素-l 的双转基因小鼠中 tau 蛋白的积累增强

• 发表时间: 2006
• 期刊: Brain Research 1094
• 作者: Samura E;Shoji M;Kawarabayashi T;Sasaki A;Matsubara E;Murakami T;Ikeda M;Ishiguro K;Saido TC;Westaway D;St. George-Hyslop P;Harigaya Y;Abe K
• 通讯作者: Abe K

Type-specific evolution of amyloid plaque and angiopathy in APPsw mice

• DOI: 10.1016/j.neulet.2005.10.087
• 发表时间: 2006-02
• 期刊: Neuroscience Letters
• 影响因子: 2.5
• 作者: Y. Harigaya;Y. Tomidokoro;M. Ikeda;A. Sasaki;T. Kawarabayashi;E. Matsubara;M. Kanai;T. Saido;S. Younkin;M. Shoji

神経原線維変化に関わるタウ遺伝子変異の多様性と共通性-変異タウ(R406W)トランスジェニックマウスにおける神経変性機序から

参与神经原纤维缠结的 tau 基因突变的多样性和共性 - 突变 tau (R406W) 转基因小鼠的神经退行性机制

• 发表时间: 2005
• 期刊: Cognition and Dementia 4・3
• 作者: Ishikawa K;Mizusawa H;池田 将樹
• 通讯作者: 池田 将樹