Role of Tau Cleavage in Tauopathy

Tau 蛋白裂解在 Tau 蛋白病中的作用

• 批准号: 8503061
• 负责人: Karen H Ashe
• 金额: $ 41.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503061
• 关键词: Alzheimer' s Disease; Americas; Aspartate; Binding Proteins; Biological; Biological Assay; Brain; Cleaved cell; Cognition; Cognitive; Data; Dementia; Dendritic Spines; Development; Drug Targeting; Foundations; Frontotemporal Dementia; Functional disorder; Glutamate Receptor; Goals; Impaired cognition; Knowledge; Learning; Link; Measures; Mediating; Memory; Memory impairment; Microtubules; Modification; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurotransmitter Receptor; Patients; Pharmaceutical Preparations; Play; Process; Rattus; Resistance; Role; Science; Staging; Synapses; Synaptic Transmission; Synaptic plasticity; Tauopathies; Testing; Transgenic Mice; Transgenic Organisms; Variant; Vertebral column; Work; brain tissue; caspase-2; cognitive function; improved; mild cognitive impairment; neuron loss; neurotoxicity; novel; prevent; relating to nervous system; synaptic function; tau Proteins; tau mutation; trafficking

This project aims to validate a novel drug target for tauopathies ¿ a group of incurable neurodegenerative conditions that includes Alzheimer¿s disease (AD). My lab previously used transgenic mice to assay the biological activity of the microtubule-binding protein tau, which aggregates to form neurofibrillary tangles, a cardinal feature of tauopathies. We discovered that cognitive dysfunction in rTg4510 mice expressing the P301L tau variant (tauP301L), linked to frontotemporal dementia, begins prior to neuron loss and occurs independently of neurofibrillary tangles or insoluble tau. Cognitive function improves when soluble transgenic tau is reduced (SantaCruz et al., Science, 2005). These results implicated some form of soluble tau in impairing cognition. Next, we showed that tauP301L and pseudo-hyperphosphorylated wild-type tau (tauEPWT) mislocalize to dendritic spines, which results in decreased synaptic transmission due to the reduction of glutamate receptors in the spines (Hoover et al., Neuron, 2010). These data suggested a mechanism by which pathological forms of tau disrupt synaptic function. In the current application, we show that a specific modification of either tauP301L or tauEPWT is necessary and sufficient for tau to mislocalize to spines. We also show that the specifically modified form to tau is elevated in the brains of patients with Mild Cognitive Impairment and AD. Here, we propose to test the hypothesis that the specifically modified form of tau disrupts synaptic function and impairs cognition in tauopathies. The successful completion of our goals will enable us to lay the biological foundation for discovering drugs that may block tau-related neurotoxicity in Alzheimer¿s disease and other tauopathies. This project intends to improve both our understanding of the processes that initiate AD and our ability to treat it in its earliest stages, by determining whether specific forms of tau interfere with neurotransmitter receptor trafficking in dendritic spines and memory function. Since these abnormal processes occur prior to the loss of neurons, these pathogenic tau species could become a target for therapies aimed at preventing tauopathies from developing into progressive, fatal dementias. If successful, the work could benefit millions of people.

该项目旨在验证一种针对 tau蛋白病（包括阿尔茨海默氏病 (AD) 在内的一组无法治愈的神经退行性疾病）的新药物靶标。我的实验室之前使用转基因小鼠来检测微管结合蛋白 tau 的生物活性，这种蛋白聚集形成神经原纤维缠结，这是 tau 病的一个主要特征。我们发现，表达 P301L tau 变体 (tauP301L) 的 rTg4510 小鼠的认知功能障碍与额颞叶痴呆有关，在神经元丢失之前就开始出现，并且独立于神经原纤维缠结或不溶性 tau 蛋白而发生。当可溶性转基因 tau 蛋白减少时，认知功能会得到改善（SantaCruz 等人，Science，2005）。这些结果表明某种形式的可溶性 tau 蛋白会损害认知。接下来，我们发现 tauP301L 和假过度磷酸化野生型 tau (tauEPWT) 错误定位于树突棘，从而导致树突棘中谷氨酸受体的减少导致突触传递减少 (Hoover et al., Neuron, 2010)。这些数据表明了 tau 蛋白的病理形式破坏突触功能的机制。在当前的应用中，我们表明，tauP301L 或 tauEPWT 的特定修饰对于 tau 错误定位到棘是必要且充分的。我们还发现，经过特殊修饰的 tau 蛋白在轻度认知障碍和 AD 患者的大脑中含量升高。 在这里，我们建议检验以下假设：tau 蛋白的特殊修饰形式会破坏 tau 蛋白病中的突触功能并损害认知。我们目标的成功完成将使我们能够为发现可以阻断阿尔茨海默病和其他 tau 病中 tau 相关神经毒性的药物奠定生物学基础。该项目旨在通过确定特定形式的 tau 蛋白是否干扰神经递质受体，提高我们对 AD 引发过程的理解以及在早期阶段治疗 AD 的能力 树突棘和记忆功能的贩运。由于这些异常过程发生在神经元损失之前，这些致病性 tau 蛋白物种可能成为旨在防止 tau 蛋白病发展为进行性致命痴呆的治疗靶标。如果成功，这项工作将使数百万人受益。