Reversal of Tau Alzheimer's hyperphosphorylation by pharmacological elevation of

描述（由研究者提供）：Tau的过度磷酸化导致阿尔茨海默病（AD）中神经元缠结（NFT）的形成，并导致痴呆症基础的突触功能障碍。减少Tau过度磷酸化是AD的治疗目标。O-GlcNAc是通过酶动态连接/去除的细胞内碳水化合物翻译后修饰。Tau被O-GlcNAc修饰，并且在人AD脑中O-GlcNAc水平降低。O-GlcNAc与特定丝氨酸/苏氨酸的磷酸化竞争，导致AD中O-GlcNAc减少可能导致Tau过度磷酸化的假设。3XTg-AD小鼠显示出Abeta斑块和与NFT负荷相关的Tau过度磷酸化的逐渐增加。我们已经证明了在3XTg-AD小鼠中与Tau过度磷酸化相关的O-GlcNAc修饰的特异性减少。我们已经证明了在体内脑O-GlcNAc水平的药理学升高首次使用水解O-GlcNAc的酶的新抑制剂。O-GlcNAc的这种升高降低了3XTg-AD小鼠中Tau在高度磷酸化表位苏氨酸212处的高度磷酸化。我们将绘制人类和小鼠Tau O-GlcNAc位点，并全面确定药理学体内O-GlcNAc水平升高对3XTg-AD小鼠中特定Tau过度磷酸化事件（通过蛋白质印迹、质谱和免疫组织化学）和NFT负荷的影响。该项目将阐明O-GlcNAc和Tau磷酸化之间的相互作用机制，证明调节AD中Tau过度磷酸化的新组分，并将调节O-GlcNAc水平的酶定义为AD中的新候选治疗靶点。

DESCRIPTION (provided by investigator): Hyperphosphorylation of Tau leads to neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) and contributes to synaptic dysfunction underlying dementia. Reduction of Tau hyperphosphorylation is a therapeutic goal in AD. O-GlcNAc is an intracellular carbohydrate post- translational modification dynamically attached/removed by enzymes. Tau is modified by O-GlcNAc, and O-GlcNAc levels are reduced in human AD brain. O-GlcNAc competes with phosphorylation at specific serines/threonines, leading to the hypothesis that reduced O-GlcNAc in AD may contribute to Tau hyperphosphorylation. The 3XTg-AD mouse displays Abeta plaques and progressively increasing hyperphosphorylation of Tau that correlates with NFT burden. We've demonstrated specific decreases in O-GlcNAc modifications that correlate with Tau hyperphosphorylation in the 3XTg-AD mouse. We've demonstrated pharmacological elevation of in vivo brain O-GlcNAc levels for the first time using a novel inhibitor of the enzyme that hydrolyzes O-GlcNAc. This elevation of O- GlcNAc reduces hyperphosphorylation of Tau at the hyperphosphorylation epitope threonine 212 in the 3XTg-AD mouse. We will map human and mouse Tau O-GlcNAc sites and comprehensively determine the influence of pharmacological in vivo elevation of O-GlcNAc levels on specific Tau hyperphosphorylation events (through western blotting, mass spectrometry, and immunohistochemistry) and NFT burden in the 3XTg-AD mouse. This project will elucidate mechanistic interplay between O-GlcNAc and phosphorylation on Tau, demonstrate a novel component regulating Tau hyperphosphorylation in AD, and define enzymes that regulate O-GlcNAc levels as novel candidate therapeutic targets in AD.