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

糖原合成酶激酶-3β(GSK-3β)在tau的磷酸化过程中起着重要作用。这一证据被认为是诱导形成神经原纤维缠结(NFT)的，在包括阿尔茨海默病在内的神经官能症中观察到。阐明GSK-3β参与神经纤维变性和神经细胞死亡的机制，开发治疗这些疾病的新方法是至关重要的。目的：探讨GSK-3β转基因小鼠细胞囊结构的免疫细胞化学变化。观察3、8、12个月时转基因小鼠脑内GSK-3β的免疫细胞化学及免疫印迹。我们检测了过表达具有固有活性的GSK-3β(S9A)的转基因小鼠的免疫细胞化学研究，发现GSK-3β在3到12个月龄时在神经细胞的胞浆和树突中的表达增加。抗体SMI-31、NF-200可降低脑和脊髓微管相关蛋白2(MAP2)的表达水平，降低神经元树突中神经丝的免疫反应性。这些结果表明，体内过表达GSK-3β导致神经细胞内磷酸化神经丝和MAP2蛋白减少，导致胞囊结构的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.