Tau-induced axonal degeneration in Alzheimer's disease and tauopathies

描述(申请人提供)：阿尔茨海默氏症和其他神经退行性疾病是与衰老相关的神经退行性疾病，代表着美国医疗系统即将面临的重大经济和治疗负担，随着人口向老龄化人口的转变，这种负担只会增加。这些疾病的特征是异常修饰的tau蛋白的病理性堆积，这与他们观察到的认知缺陷密切相关。由于肌萎缩侧索硬化症的根本原因尚不清楚，因此很难开发有效的治疗干预措施。一些最早的病理改变，特别是在AD中，遵循“死后”模式，在这种模式下，轴突首先表现出异常的结构变化。导致轴突变性的一个可能的致病因素是tau蛋白，因为它在维持轴突功能方面起着关键作用。事实上，使用人体组织和动物模型系统的研究表明，tau异常和轴突退化是阿尔茨海默病早期退行性后遗症的相互关联的组成部分。我们的初步数据表明，与疾病相关的tau修饰暴露了该蛋白的氨基末端，导致培养的神经元和体内的轴突功能障碍和变性。这项建议的主要目标是测试tau的疾病相关异常是否会导致轴突变性。三个独立的具体目标被提出，以采取多方面的方法，旨在解决这一假设。目的1将在原代培养的海马神经元中建立tau修饰的相对贡献和与tau诱导的轴突变性相关的分子事件，以及一种新的基于病毒载体的大鼠模型。目的2将明确tau蛋白与与tau诱导的轴突功能障碍相关的酶(即蛋白磷酸酶1和糖原合成酶激酶3β)之间的功能关系。最后，目标3将利用从非痴呆对照到严重痴呆的病例的尸检组织，确定tau蛋白的异常形式与人类AD进展中的轴突变性之间的关系。如果成功，这些研究将确定tau诱导的轴突功能障碍/退化的分子机制，该机制可能成为AD患者以及其他tauopathy患者的疾病修改治疗干预措施的目标。

DESCRIPTION (provided by applicant): Alzheimer's disease and other tauopathies are aging-related neurodegenerative diseases that are representative of a significant impending economic and treatment burden for the US healthcare system that will only increase as the population shifts to a more aged demographic. These diseases are characterized by the pathological accumulation of abnormally modified tau proteins, which is closely linked to their observed cognitive deficits. Since the underlying causes of tauopathies remain unknown, it is accordingly difficult to develop effective therapeutic interventions. Some of the earliest pathological changes, especially in AD, follow a "dying-back" pattern in which axons are the first to exhibit abnormal structural changes. A likely pathogenic factor contributing to axonal degeneration is the protein tau, as it is critical in maintaining axonal function. Indeed, studies using human tissue and animal model systems suggest that tau abnormalities and axonal degeneration are interconnected components of the early degenerative sequelae of AD. Our preliminary data indicate that disease-related modifications of tau that expose the amino terminus of the protein cause axonal dysfunction and degeneration in cultured neurons and in vivo. The primary goal of this proposal is to test whether disease-associated abnormalities in tau can induce axonal degeneration. Three independent specific aims are proposed to take a multifaceted approach aimed at addressing this hypothesis. Aim 1 will establish the relative contribution of tau modifications and the molecular events associated with tau-induced axon degeneration in primary cultured hippocampal neurons as well as a novel, viral vector-based rat model. Aim 2 will define the functional relationship between tau protein and enzymes linked to tau-induced axonal dysfunction (i.e. protein phosphatase 1 and glycogen synthase kinase 3β). Lastly, Aim 3 will define the relationship between abnormal forms of tau protein and axonal degeneration in the progression of human AD using post-mortem tissue from cases ranging between non-demented controls to severely demented AD. If successful, these studies will identify a molecular mechanism for tau-induced axon dysfunction/degeneration that could be targeted for disease-modifying therapeutic interventions in AD patients, as well as those suffering from other tauopathies.