Role of Tau Cleavage in Tauopathy

该项目旨在验证tau蛋白病的一种新型药物靶标，tau蛋白病是一组无法治愈的神经退行性疾病，包括阿尔茨海默病（AD）。我的实验室以前使用转基因小鼠来分析微管结合蛋白tau的生物活性，这种蛋白聚集形成神经元缠结，这是tau蛋白病的一个主要特征。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，在神经元丢失之前开始，并且独立于神经元缠结或不溶性tau。当可溶性转基因tau减少时，认知功能改善（SantaCruz et al.，Science，2005）。这些结果暗示了某种形式的可溶性tau蛋白损害认知。接下来，我们显示了tauP301L和假过度磷酸化的野生型tau（tauEPWT）错误定位于树突棘，这由于棘中谷氨酸受体的减少而导致突触传递减少（Hoover等人，Neuron，2010）。这些数据表明病理形式的tau破坏突触功能的机制。在目前的应用中，我们表明，一个特定的修改，无论是tauP301L或tauEPWT是必要的和足够的tau错误定位到刺。我们还表明，在轻度认知障碍和AD患者的大脑中，tau的特异性修饰形式升高。 在这里，我们建议测试的假设，特别是修改形式的tau破坏突触功能和损害认知的tau蛋白病。我们目标的成功完成将使我们能够为发现可能阻断阿尔茨海默病和其他tau蛋白病中tau蛋白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是否干扰神经递质受体，提高我们对引发AD的过程的理解以及我们在其早期阶段治疗AD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，这些致病性tau物质可能成为旨在预防tau蛋白病发展为进行性、致命性痴呆的治疗的靶点。如果成功，这项工作将惠及数百万人。

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.