Alterations in System Integrity Associated with Tauopathy Development

与 Tau 病发展相关的系统完整性的改变

• 批准号: 6966712
• 负责人: PETER P DAVIES
• 金额: $ 16.35万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966712
• 关键词: amyloid proteins; calmodulin dependent protein kinase; chemical aggregate; genetically modified animals; glutamate receptor; hippocampus; immunocytochemistry; laboratory mouse; long term potentiation; neural transmission; neuropharmacologic agent; phosphorylation; protein localization; protein protein interaction; pyramidal cells; tau proteins

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.

hTau 小鼠提供了一个研究有关 tau 病理学发展的一些最基本问题的机会。在项目 4 中，我们将通过测量基础突触传递和长期增强来检验 CA1 锥体神经元中过度磷酸化 tau 蛋白的积累将损害这些细胞的突触生理学的假设。将检查来自四个规定年龄的 hTau 小鼠半脑的海马，并将结果与​​从年龄匹配的小鼠加人 tau 小鼠 (8c) 和非转基因小鼠（所有同窝小鼠）获得的结果进行比较。具体目标 1 的生理学将通过谷氨酸受体、其磷酸化状态和相关蛋白水平（特别是钙-钙调蛋白依赖性蛋白）的生化和免疫组织化学研究来补充 激酶 II (CamKII)。将检查 CamKII 的活性并确定其与人类 tau 蛋白的关联。这些分析将在用于电生理学的另一半大脑上进行。我们将尝试直接检验这样的假设：cdk5 或 GS​​K3beta 引起的 tau 过度磷酸化会损害 hTau 小鼠 CA1 神经元的突触生理学。项目 5 将确定剂量和给药途径 锂（一种 GSK3 抑制剂）和 roscovitine（一种 cdk5 抑制剂）可减少 hTau 小鼠的 tau 磷酸化。相同的剂量和给药途径将用于评估这些治疗对突触生理学和生物化学的影响。如果项目 5 下的工作表明 tau 聚集抑制剂 NN13 对于 hTau 小鼠来说是一种可行的治疗方法，那么该抑制剂的作用也将得到研究。我们将检验这样的假设：hTau 小鼠中 Abeta 浓度的升高会加速突触传递缺陷的出现。 Abeta 浓度将通过在 Tg2576 APP 转基因中繁殖而升高，并且将对不同年龄的 APP+/hTau+、APP+/hTau-、APP-/hTau+ 和 APP-/hTau- 小鼠进行生理学和生物化学分析。在此计划项目应用中，正在使用多种技术 用于表征 tau 蛋白病的分子细节，以及特定神经元群的详细形态。我们将尝试调节病理学的发展，并探索与 Abeta 可能的相互作用。以如此全面的调查为中心，该项目将受益匪浅。