Alterations in System Integrity Associated with Tauopathy Development

HTau小鼠提供了一个机会来研究一些关于tau病理发展的最基本的问题。在项目4中，我们将通过测量基础突触传递和长时程增强来验证假设，即过度磷酸化的tau在CA1锥体神经元中的积累将损害这些细胞的突触生理。研究人员将检测四个特定年龄的hTau小鼠的半脑中的海马神经元，并将结果与年龄匹配的小鼠加人Tau小鼠(8c)和非转基因小鼠的结果进行比较，这些小鼠都是小鼠。谷氨酸受体的生化和免疫组织化学研究、谷氨酸受体的磷酸化状态和相关蛋白的水平，特别是钙-钙调蛋白依赖蛋白的水平，将补充特定目标1的生理学。 激酶II(CaMKII)。将检测CaMKII的活性，并确定其与人类tau的关系。这些分析将在用于电生理的另一半大脑上进行。我们将尝试直接测试这一假设，即是由CDK5或GSK3β过度磷酸化的tau损害了hTau小鼠CA1神经元的突触生理。项目5将确定给药剂量和给药途径 锂(GSK3抑制剂)和罗斯科维汀(CDK5抑制剂)可减少hTau小鼠tau的磷酸化。同样的剂量和给药途径将被用来评估这些治疗对突触生理和生化的影响。如果项目5的工作表明tau聚集抑制剂NN13是一种可行的治疗hTau小鼠的方法，那么它的效果也将被调查。我们将验证这一假设，即hTau小鼠体内Abeta浓度的升高会加速突触传递缺陷的出现。通过在Tg2576 APP转基因小鼠中的繁殖，将提高Aβ浓度，并对不同年龄的APP+/hTau+、APP+/hTau-、APP-/hTau+和APP-/hTau-小鼠进行生理和生化检查。在这个方案项目应用中，各种各样的技术正在被 用于表征互变的分子细节，以及特定神经元群体的详细形态。将尝试调节病理的发展，并将探索与Abeta的可能相互作用。以这样的全面调查为中心，这一项目将受益匪浅。

The hTau mouse offers an opportunity to examine some of the most basic questions regarding the development of tau pathology. In Project 4, we will test the hypothesis that the accumulation of hyperphosphorylated tau in CA1 pyramidal neurons will impair the synaptic physiology of these cells, by measuring basal synaptic transmission and long term potentiation. Hippocampii from hemibrains of hTau mice of four defined ages will be examined, and the results will be compared to those obtained from age-matched mouse plus human tau mice (8c) and non-transgenic mice, all littermates. The physiology of specific aim 1 will be complemented by biochemical and immunohistochemical studies of glutamate receptors, their phosphorylation status, and levels of associated proteins, in particular calcium-calmodulin dependent protein kinase II (CamKII). The activity of CamKII will be examined and its association with human tau determined. These analyses will be performed on the other half of the brains used for electrophysiology. We will attempt to directly test the hypothesis that it is tau hyperphosphorylation by either cdk5 or GSK3beta that impairs the synaptic physiology of CA1 neurons in hTau mice. Project 5 will define doses and routes of administration of lithium (a GSK3 inhibitor) and roscovitine (a cdk5 inhibitor) that reduce tau phosphorylation in the hTau mice. The same doses and routes of administration will be used to assess the effects of these treatments on synaptic physiology and biochemistry. The effects of a tau aggregation inhibitor, NN13, will also be investigated, if work under project 5 suggests this is a viable treatment for the hTau mouse. We will test the hypothesis that elevation of Abeta concentrations in hTau mice accelerates the appearance of defects in synaptic transmission. Abeta concentrations will be elevated by breeding in the Tg2576 APP transgene, and both physiology and biochemistry will be performed on APP+/hTau+, APP+/hTau-, APP-/hTau+ and APP-/hTau- mice of different ages. In this program project application, a wide variety of techniques are being employed to characterize the molecular details of the tauopathy, as well as the detailed morphology of specific neuronal populations. Attempts will be made to modulate the development of the pathology, and the possible interaction with Abeta will be explored. This project will benefit enormously by being centered in such a comprehensive investigation.