Role of Tau Cleavage in Tauopathy

Tau 蛋白裂解在 Tau 蛋白病中的作用

• 批准号: 8798702
• 负责人: Karen H Ashe
• 金额: $ 36.12万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8798702
• 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; targeted treatment; 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治疗包括阿尔茨海默病和S病(AD)在内的一组不可治愈的神经退行性疾病的新药靶点。我的实验室之前曾使用转基因小鼠来测试微管结合蛋白tau的生物活性，它聚集在一起形成神经原纤维缠结，这是tau病的基本特征。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部痴呆有关，开始于神经元丧失之前，独立于神经原纤维缠结或不溶性tau发生。当可溶性转基因tau减少时，认知功能得到改善(SantaCruz等人，《科学》，2005年)。这些结果表明，某种形式的可溶性tau会损害认知。接下来，我们发现tauP301L和伪过度磷酸化野生型tau(TauEPWT)错误定位于树突棘，这导致突触传递减少，这是由于脊椎中谷氨酸受体的减少(Hoover等人，Neuron，2010)。这些数据表明了一种病理形式的tau破坏突触功能的机制。在目前的应用中，我们证明了tauP301L或tauEPWT的特定修饰对于tau错位定位到脊柱是必要的，也是充分的。我们还发现，在轻度认知障碍和AD患者的大脑中，tau的特异性修饰形式是升高的。 在这里，我们建议检验这样一种假设，即tau的特定修饰形式扰乱了突触功能，并损害了tauopathy的认知。我们的目标的成功完成将使我们能够为发现可能阻断与tau相关的神经毒性的药物奠定生物学基础，这些药物可能会抑制阿尔茨海默病、S病和其他tau病的神经毒性。这个项目旨在通过确定特定形式的tau是否干扰神经递质受体，来提高我们对启动AD的过程的理解，以及我们在AD早期阶段治疗它的能力。 树突棘的运输和记忆功能。由于这些异常过程发生在神经元丧失之前，这些致病tau物种可能成为旨在防止tauopathy发展为进行性、致命性痴呆的治疗目标。如果成功，这项工作可能会让数百万人受益。