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

糖原合成酶激酶-3 β（Glycogen synthase kinase-3 β，GSK-3β）在tau蛋白磷酸化过程中起重要作用。这一证据被认为是诱导形成在包括阿尔茨海默病在内的tau蛋白病中观察到的神经元缠结（NFT）。阐明GSK-3β参与NFT和神经元细胞死亡的机制，对于开发新的治疗方法具有重要意义。目的：观察GSK-3β转基因小鼠细胞形态结构的免疫细胞化学变化。观察GSK-3β转基因小鼠3、8、12月龄脑组织的免疫细胞化学和Western blot。我们对过表达组成型活性GSK-3β（S9 A）的转基因小鼠进行了免疫细胞化学研究，结果表明，GSK-3β在3 ~ 12月龄的小鼠神经细胞胞浆和树突中的表达呈年龄依赖性增加。脑和脊髓中微管相关蛋白2（MAP 2）水平的降低以及神经元树突中神经丝的SMI-31、NF-200免疫反应性的降低。这些结果提示GSK-3β在体内过表达可导致神经元细胞内磷酸化神经丝和MAP 2蛋白减少，导致细胞骨架结构异常改变和神经元功能障碍。

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.