Elucidating the role of AD risk factor Pyk2 in tau-induced synaptic dysfunction

阐明 AD 危险因子 Pyk2 在 tau 诱导的突触功能障碍中的作用

• 批准号: 10371865
• 负责人: Alex Harrison Brody
• 金额: $ 3.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-04 至 2022-03-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371865
• 关键词: Acute; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Animals; Binding Proteins; Brain; CRISPR/Cas technology; Cause of Death; Cells; Cessation of life; Characteristics; Clinical; Data; Dendrites; Development; Disease; Disease Progression; Electrophysiology (science); Exposure to; Failure; Functional disorder; Future; Genetic; Hippocampus (Brain); Histologic; Human; Impairment; In Vitro; Individual; Label; Late Onset Alzheimer Disease; Link; Mediating; Memory impairment; Messenger RNA; Modeling; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; PTK2B gene; Pathogenesis; Pathology; Pharmacology; Phenotype; Phosphotransferases; Play; Population; Preparation; Production; Proteins; Proteomics; Research Design; Risk Factors; Role; Series; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Synaptosomes; Tauopathies; Thick; Toxic effect; United States; Work; aged; density; dentate gyrus; effective therapy; experimental study; genetic risk factor; genome wide association study; global health; hyperphosphorylated tau; in vivo; induced pluripotent stem cell; insight; mutant; neuron loss; novel; prevent; receptor; tau Proteins; tau dysfunction; tau phosphorylation; tau-1; therapy design

PROJECT SUMMARY Alzheimer’s disease (AD) currently affects an estimated 5.8 million individuals in the United States, a number that is expected to grow to 7 million by 2050. In the US AD is the sixth leading cause of death overall and the fifth leading cause of death in individuals 65 and older. There are currently no disease modifying therapies known to slow or halt AD progression, thus a better understanding of AD pathogenesis is essential to address an impeding global health crisis. While it is understood that amyloid beta (Aβ) leads to progressive synapse loss and is a major contributing feature of AD, it is not well-understood how Aβ signaling triggers tau pathology. Studies designed to reveal how Aβ contributes to this second equally critical component of the disease are critical. Multiple genome wide association studies have identified Pyk2 (PTK2B) as a genetic risk factor for late- onset Alzheimer’s disease, which comprises a vast majority of AD cases. Pyk2 is both activated by Aβ signaling and is required for the presentation of a number of Aβ associated phenotypes including synapse loss and memory impairment. However, preliminary data I have gathered suggests that Pyk2, which has been demonstrated to interact both directly and indirectly with tau, is protective against tau-mediated neuronal dysfunction. The Aims of this proposal will determine how Pyk2 functions to protect neurons from tau-mediated damage and how Aβ may modulate that function in a way that diminishes this protective capacity. Aim 1 will investigate the role of Pyk2 in protecting neurons against tau-mediated synaptic dysfunction and toxicity. Experiment 1a will use an electrophysiological approach to determine whether Pyk2 expression is protective against tau-mediated impairments of synaptic transmission and plasticity in a well-described tauopathy animal model. Experiment 1b and Experiment 1c will determine whether Pyk2 expression modulates tau-associated synaptic disorganization in vitro and in vivo, respectively. Aim 2 will investigate Pyk2’s role in regulating Aβ-induced tau dysfunction and how that role is modulated by Aβ. Experiment 2a will determine whether Pyk2 expression is protective against Aβ-induced tau hyperphosphorylation and dendritic mislocalization in human neurons. Experiment 2b will assess how Aβ signaling modulates the expression and localization of Pyk2. Experiment 2c will determine how Pyk2 protein binding partners are modulated by Aβ signaling. To the best of our knowledge, these experiments represent the first attempts to understand Pyk2’s role in protecting synapses against tau-mediated damage and how that might be perturbed in the presence of Aβ. These experiments will yield critical information regarding the link between Aβ and tau and will likely reveal novel protein targets for future AD therapies.

项目摘要 阿尔茨海默病（AD）目前在美国影响估计580万个体， 预计到2050年将增长到700万。在美国，AD是第六大死亡原因， 是65岁及以上人群的第五大死因。目前没有已知的疾病修饰疗法 因此，更好地了解AD的发病机制对于解决AD的发病机制至关重要。 阻碍全球健康危机。虽然淀粉样蛋白β（Aβ）导致进行性突触丧失， 并且是AD的主要贡献特征，但还不清楚Aβ信号传导如何触发tau病理。 旨在揭示Aβ如何促进这种疾病的第二个同样重要的组成部分的研究是 很危险多个全基因组关联研究已将Pyk2（PTK2B）确定为晚期乳腺癌的遗传风险因素。 阿尔茨海默病是一种常见的疾病，它包括绝大多数AD病例。Pyk2既被Aβ信号激活， 并且是呈现许多Aβ相关表型所必需的，包括突触丢失和 记忆受损然而，我收集的初步数据表明，Pyk2，这已经是 证明与tau蛋白直接和间接相互作用，对tau蛋白介导的神经元损伤具有保护作用。 功能障碍该提案的目的将确定Pyk2如何发挥作用以保护神经元免受tau介导的损伤。 以及Aβ如何以降低这种保护能力的方式调节这种功能。 目的1将研究Pyk 2在保护神经元免受tau介导的突触功能障碍中的作用。 和毒性。实验1a将使用电生理学方法来确定Pyk2表达是否 在一个众所周知的研究中， tau蛋白病动物模型。实验1b和实验1c将确定Pyk2表达是否调节 分别在体外和体内观察tau蛋白相关的突触紊乱。 目的2将研究Pyk2在调节Aβ诱导的tau蛋白功能障碍中的作用，以及这种作用是如何被激活的。 由Aβ调节。实验2a将确定Pyk2表达是否对Aβ诱导的tau蛋白具有保护作用 过度磷酸化和树突错误定位。实验2b将评估Aβ 信号传导调节Pyk2的表达和定位。实验2c将确定Pyk2蛋白如何 结合伴侣受Aβ信号传导调节。 据我们所知，这些实验代表了首次尝试了解Pyk2在 保护突触免受tau蛋白介导的损伤，以及在Aβ存在的情况下，这种损伤可能会受到干扰。 这些实验将产生关于Aβ和tau之间联系的关键信息，并可能揭示新的 未来AD治疗的蛋白质靶点。