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

阿尔茨海默病和 tau 病中 Tau 诱导的轴突变性

• 批准号: 8695612
• 负责人: Nicholas M Kanaan
• 金额: $ 33.31万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695612
• 关键词: Address; Affect; Alzheimer' s Disease; Animal Model; Appearance; Axon; Axonal Transport; Back; Biological Models; Brain; Clinical; Cognitive deficits; Cytoskeleton; Data; Dementia; Demographic Aging; Deposition; Disease; Economics; Enzymes; Event; Exhibits; Functional disorder; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; Health; Healthcare Systems; Hippocampus (Brain); Human; Human Development; Impaired cognition; In Vitro; Light; Link; Mediating; Methods; Microfluidics; Microtubule-Associated Proteins; Modeling; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropathy; Neuropil Threads; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phosphoric Monoester Hydrolases; Population; Protein phosphatase; Proteins; Publishing; Rattus; Recombinant Proteins; Recombinant adeno-associated virus (rAAV); Relative (related person); Resources; Role; Signal Transduction; Signaling Molecule; Squid; Symptoms; Synapses; Tauopathies; Temporal Lobe; Testing; Therapeutic Intervention; Time; Tissue Model; Tissues; Viral Vector; age related; aging population; axonal degeneration; axoplasm; base; frontal lobe; human tissue; in vitro Assay; in vivo; in vivo imaging; inhibitor/antagonist; insight; longitudinal analysis; middle age; neuron loss; neuronal cell body; neurotoxicity; novel; prevent; relating to nervous system; research study; tau Proteins; tau function; tau mutation; therapeutic target

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.

描述（由申请人提供）：阿尔茨海默病和其他tau蛋白病是衰老相关的神经退行性疾病，代表美国医疗保健系统即将面临的重大经济和治疗负担，随着人口向更老龄化的人口转变，这种负担只会增加。这些疾病的特征在于异常修饰的tau蛋白的病理性积累，这与其观察到的认知缺陷密切相关。由于tau蛋白病的根本原因仍然未知，因此难以开发有效的治疗干预。一些最早的病理变化，特别是在AD中，遵循“回退”模式，其中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至关重要。事实上，使用人体组织和动物模型系统的研究表明，tau异常和轴突变性是AD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，暴露蛋白质氨基末端的疾病相关的tau修饰在培养的神经元和体内引起轴突功能障碍和变性。该提案的主要目标是测试tau蛋白的疾病相关异常是否会诱导轴突变性。提出了三个独立的具体目标，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将确定tau蛋白和与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将使用非痴呆对照至严重痴呆AD病例的尸检组织，确定人类AD进展中tau蛋白异常形式与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/变性的分子机制，可以靶向AD患者以及患有其他tau蛋白病的患者的疾病修饰治疗干预。