Tau-PI3Kalpha Complex in Regulation of PI3K/Akt-dependent Neuronal Function and Survival

Tau-PI3Kalpha 复合物调节 PI3K/Akt 依赖性神经元功能和存活

• 批准号: 10710161
• 负责人: Richard A. Anderson
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710161
• 关键词: Affect; Affinity; Aging; Alzheimer' s Disease; Amino Acids; Axon; Axonal Transport; Binding; Cell Communication; Cell Death; Cell Line; Cell Survival; Cell physiology; Cells; Complex; Data; Dendrites; Disease; Disease Progression; Endosomes; FRAP1 gene; Fluorescein-5-isothiocyanate; Foundations; Generations; Growth Factor; Hippocampus; Impairment; In Vitro; Induced pluripotent stem cell derived neurons; Insulin; Insulin Receptor; Investigation; Label; Link; MAP4; MAPT gene; Maps; Mediating; Microtubules; Modeling; Molecular; Mutate; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Magnetic Resonance; PI3 gene; PIK3CG gene; Pathogenicity; Pathologic; Pathology; Peptides; Permeability; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Spatial Distribution; Structure; Tauopathies; Testing; Therapeutic; Work; hyperphosphorylated tau; in vivo; insulin signaling; knock-down; mutant; neurofibrillary tangle formation; neuron loss; neuronal survival; neurotoxicity; neurotransmission; receptor; scaffold; tau Proteins; tau aggregation; tau interaction; tau microtubule binding domain; tau mutation; tau-1; therapeutic development; Affect; Affinity; Aging; Alzheimer' s Disease; Amino Acids; Axon; Axonal Transport; Binding; Cell Communication; Cell Death; Cell Line; Cell Survival; Cell physiology; Cells; Complex; Data; Dendrites; Disease; Disease Progression; Endosomes; FRAP1 gene; Fluorescein-5-isothiocyanate; Foundations; Generations; Growth Factor; Hippocampus; Impairment; In Vitro; Induced pluripotent stem cell derived neurons; Insulin; Insulin Receptor; Investigation; Label; Link; MAP4; MAPT gene; Maps; Mediating; Microtubules; Modeling; Molecular; Mutate; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Magnetic Resonance; PI3 gene; PIK3CG gene; Pathogenicity; Pathologic; Pathology; Peptides; Permeability; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Spatial Distribution; Structure; Tauopathies; Testing; Therapeutic; Work; hyperphosphorylated tau; in vivo; insulin signaling; knock-down; mutant; neurofibrillary tangle formation; neuron loss; neuronal survival; neurotoxicity; neurotransmission; receptor; scaffold; tau Proteins; tau aggregation; tau interaction; tau microtubule binding domain; tau mutation; tau-1; therapeutic development

PROJECT SUMMARY Tau pathologies including Alzheimer’s disease are the most prevalent and complex neurodegenerative diseases of aging that will likely reach 115 million globally by 2050(6) yet, there are no therapeutic drugs to treat this disease, except a controversial recently approved drug(7). Though the formation of intracellular neurofibrillary tangles (NFTs) from the hyperphosphorylated tau protein in the cortical and hippocampal regions is a key pathological hallmark of tau pathologies, the precise mechanisms of how hyperphosphorylated tau impact survival signaling in neurons is lacking. Recently we have shown that the PI3K/Akt survival signaling pathway is controlled by the non-neuronal type microtubule-associated protein 4 (MAP4) that directly interacts with PI3K via its microtubule-binding domain (MTBD)(9). The PI3K interaction with MAP4 controls the PI3K association with activated receptor kinases that are required for PI3K activation, PI3,4,5P3 generation, and Akt activation(9). The MTBD of MAP4 that binds PI3K shows strikingly high homology with the microtubule- binding domain of the neuronal microtubule-associated proteins tau and MAP2, stimulating the hypothesis that tau and MAP2 substitute for MAP4 control of PI3K/Akt survival signaling in neurons. Our preliminary data shows the association between tau and PI3K in primary neurons, induced pluripotent stem cells-derived neurons, and a neuronal cell line. The siRNA-mediated knockdown of tau blocked insulin stimulated Akt activation. We hypothesize that tau scaffold the PI3K along microtubules in axons and dendrites to control growth factor stimulated PI3K/Akt survival signaling of neurons. Increased tau hyperphosphorylation and its aggregation during Alzheimer’s disease progression impairs the spatial organization of PI3K along microtubules resulting in loss of growth factor stimulated PI3K/Akt signaling that is critical for neuronal cell survival and function. The focus of proposed study is to establish and understand mechanistically tau’s role in the PI3K/Akt signaling and define the PI3K interaction sites in tau. The interaction between PI3K and tau will be used to define the interaction sites for PI3K in the MTBD of tau and investigate if these sites coincide with pathogenic mutants and hyperphosphorylation sites in the MTBD of tau. We will define the effect of tau loss on spatial distribution, co-localization and interaction of PI3K with activated receptors in axons and dendrites, and effect on growth factor stimulated PI3,4,5P3 generation and Akt activation. This will be further substantiated by a systemic investigation of the impact of expressing mutant tau that is deficient on PI3K binding and the disruption of PI3K-tau interaction by cell permeable peptides on spatial PI3K/Akt signaling and survival of neurons.

项目摘要 包括阿尔茨海默氏病在内的TAU病理是最普遍，最复杂的神经退行性疾病 到2050年（6）的衰老可能会达到全球1.15亿次，但是没有治疗药物可以治疗这种药物 疾病，除了有争议的最近批准的药物（7）。虽然细胞内神经原纤维的形成 从皮质和海马区域中的高磷酸化tau蛋白的缠结（NFT）是关键 tau病理学的病理标志，这是高磷酸化tau撞击的精确机制 缺乏神经元中的生存信号传导。最近，我们证明了PI3K/AKT存活信号传导 途径由非神经型微管相关蛋白4（MAP4）控制，该蛋白质直接相互作用 使用PI3K通过其微管结合域（MTBD）（9）。与MAP4的PI3K相互作用控制PI3K 与PI3K激活，PI3,4,53生成和激活的接收器激酶相关 Akt激活（9）。结合PI3K的MAP4的MTBD与微管表现出极高的同源性 神经元微管相关蛋白Tau和Map2的结合结构域，刺激了以下假设 TAU和MAP2代替神经元中PI3K/AKT存活信号的MAP4控制。我们的初步数据显示 tau和pi3k在原发性神经元中，诱导多能干细胞衍生的神经元的关联，以及 神经元细胞系。 siRNA介导的tau敲低阻断胰岛素刺激了Akt激活。 我们假设tau沿轴突和树突的微管沿微管脚手架以控制生长因子 刺激神经元的PI3K/AKT存活信号传导。 tau高磷酸化及其聚集 在阿尔茨海默氏病的过程中，沿微管的PI3K的空间组织损害了导致的PI3K 在生长因子损失中，刺激了对神经元细胞存活和功能至关重要的PI3K/AKT信号。 拟议的研究的重点是从机械上建立和理解tau在PI3K/AKT信号中的作用 并定义tau中的PI3K相互作用位点。 PI3K和Tau之间的相互作用将用于定义 pi3k在tau的MTBD中的相互作用位点，并研究这些位点是否与致病突变体一致 tau的MTBD中的高磷酸化位点。我们将定义tau损失对空间分布的影响， PI3K与轴突和树突中激活的接收器的共定位和相互作用，对生长的影响 因子刺激PI3,4,53的生成和Akt激活。这将通过系统性进一步证实 对表达突变体Tau的影响的研究，该突变体对PI3KA结合和破坏的影响 PI3K-TAU通过可渗透性的细胞相互作用在空间PI3K/AKT信号传导和神经元的存活率上。