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: 8928037
• 负责人: Nicholas M Kanaan
• 金额: $ 37.87万
• 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/8928037
• 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; 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 3�). 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（由适用提供）：阿尔茨海默氏病和其他tauopathies是与衰老有关的神经退行性疾病，这些疾病代表了美国医疗保健系统的重大经济和治疗燃烧，只会随着人口转移到更老的人口统计学而增加。这些疾病的特征是绝对修饰的tau蛋白的病理积累，这与它们观察到的认知缺陷密切相关。由于扭曲病的根本原因尚不清楚，因此很难制定有效的治疗干预措施。一些最早的病理变化，尤其是在AD中，遵循一种“垂死的”模式，其中轴突是第一个存在异常结构变化的轴突。有助于轴突变性的一种病原因子是蛋白质TAU，因为它对于维持轴突功能至关重要。实际上，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早期变性后遗症的互连成分。我们的初步数据表明，暴露于蛋白质的氨基末端的Tau的疾病相关修饰会导致轴突功能障碍和培养神经元和体内变性。该提案的主要目的是测试与疾病相关的TAU异常是否可以诱导轴突变性。提出了三个独立的特定目标，以采用旨在解决这一假设的多方面方法。 AIM 1将建立TAU修饰的相对贡献以及与TAU诱导的轴突变性相关的分子事件在原代培养的海马神经元中以及一种新型的基于病毒载体的大鼠模型。 AIM 2将定义与Tau诱导的轴突功能障碍相关的tau蛋白与酶（即蛋白磷酸酶1和糖原合成酶激酶3.）之间的功能关系。最后，AIM 3将使用验尸组织与非痴呆对照之间的病例与严重痴呆的AD之间的病例定义人AD的异常形式与轴突变性之间的关系。如果成功，这些研究将确定一种分子机制，用于tau诱导的轴突功能障碍/变性，该机制可用于改善AD患者的治疗干预措施以及患有其他tauopathies的疾病的治疗干预措施。