O-GlcNAcylation of tau: a link between glucose metabolism and neurodegeneration

脑内tau蛋白异常过度磷酸化和聚集是神经退行性变的关键 阿尔茨海默病(AD)。阿尔茨海默病患者的大脑葡萄糖摄取/代谢受损，这被认为是导致 神经退行性变。然而，这种损伤如何导致神经退行性变尚不清楚。这个 这个项目的具体目标是揭示tau O-GlcN酰化[一种独特的类型]的性质和功能作用 将β-N-乙酰氨基葡萄糖(GlcNAc)连接到丝氨酸或苏氨酸残基的O-糖基化 蛋白质]，并揭示阿尔茨海默病大脑葡萄糖摄取/代谢受损的机制 会导致神经退化。这项建议的长期目标是了解这一机制 阿尔茨海默病的神经退行性变的研究，并在此基础上制定策略以预防和治疗 疾病。因此，本研究的具体目标是：(1)绘制tau的O-GlcN酰化位点图，并测定其变化。 阿尔茨海默病脑内tau O-GlcN酰化。Tau O-GlcN酰化改变的根本原因也将是 比较脑内UDP-GlcNAc水平及O-GlcNAc转移酶和O-GlcNAcase活性 在AD和控制之间。(2)研究牛磺酸的O-GlcN酰化和磷酸化之间的相互作用 无论是在体外还是在分化的PC12细胞中。Tau O-GlcN酰化的功能作用将通过 测定其微管结合和组装活性，并检测细胞形态和细胞器 Tau O-GlcN酰化改变后的转运。(3)探讨脑损伤的分子机制。 脑葡萄糖摄取/代谢参与阿尔茨海默病的神经退变。两种损伤动物模型的建立 脑葡萄糖摄取/代谢抑制小鼠和小鼠脑室注射 细胞松弛素B将被用来研究它对tau O-GlcN酰化和磷酸化的影响。确切的角色是 O-GlcN酰化在低糖诱导的tau蛋白过度磷酸化和神经变性中的作用 小鼠大脑的摄取/新陈代谢也将被阐明。这些研究将揭示地球的本质和 Tau O-GlcN酰化及其失调在AD脑中的作用及机制 阿尔茨海默病患者脑内葡萄糖摄取/代谢受损导致神经退行性变。完成 这些研究将对阿尔茨海默病的神经退变机制提供新的认识和帮助。 预防和治疗阿尔茨海默病和可能其他神经退行性疾病的新策略。

Abnormal hyperphosphorylation and aggregation of tau protein in the brain are critical to neurodegeneration of Alzheimer diesease (AD). Glucose uptake/metabolism is impaired in AD brain, which is believed to cause neurodegeneration. However, how this impairment contributes to neurodegeneration is unknown. The specific goal of this project is to reveal the nature and functional role of tau O-GlcNAcylation [a unique type of O-glycosylation by which beta-N-acetylglucosamine (GlcNAc) is linked to serine or threonine residues of proteins] and to uncover the mechanism by which impaired brain glucose uptake/metabolism of AD contributes to neurodegeneration. The long-term objective of this proposal is to understand the mechanism of neurodegeneration in AD and, based on this knowledge, to develop strategies to prevent and treat the disease. Hence, the specific aims are: (1) Map the O-GlcNAcylation sites of tau and determine the change of tau O-GlcNAcylation in AD brain. The underlying cause of the change in tau O-GlcNAcylation will also be studied by comparing brain level of UDP-GlcNAc and activities of O-GlcNAc transferase and O-GlcNAcase between AD and controls. (2) Study the interactions between O-GlcNAcylation and phosphorylation of tau both in vitro and in differentiated PC12 cells. The functional role of tau O-GlcNAcylation will be studied by measuring its microtubule-binding and -assembly activities and examining cell morphology and organelle transport upon alteration of tau O-GlcNAcylation. (3) Investigate the molecular mechanism by which impaired brain glucose uptake/metabolism contributes to neurodegeneration of AD. Two animal models of impaired brain glucose uptake/metabolism¿fasted mice and mice after intracerebroventricular injection of cytochalasin B¿will be used to study its effects on tau O-GlcNAcylation and phosphorylation. The exact role of O-GlcNAcylation in tau hyperphosphorylation and neurodegeneration induced by low glucose uptake/metabolism will also be elucidated in the mouse brains. These studies will reveal the nature and functional role of tau O-GlcNAcylation and its dysregulation in AD brain and uncover the mechanism by which impaired brain glucose uptake/metabolism of AD contributes to neurodegeneration. Completion of these studies will provide new insight into the mechanism of neurodegeneration of AD and help develop novel strategies to prevent and treat AD and probably other neurodegenerative disorders.