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

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 包括阿尔茨海默病在内的Tau病理是最普遍和复杂的神经退行性疾病 到2050年，全球老龄化人口可能达到1.15亿（6），但没有治疗药物来治疗这一问题。 疾病，除了最近批准的有争议的药物（7）。虽然细胞内神经细胞的形成 在皮质和海马区，来自过度磷酸化tau蛋白的神经纤维缠结（NFT）是一个关键， tau病理学的病理标志，过度磷酸化tau如何影响 神经元中缺乏存活信号。最近，我们发现PI 3 K/Akt存活信号通路 非神经元型微管相关蛋白4（MAP 4）直接与神经元相互作用， 通过其微管结合域（MTBD）与PI 3 K结合（9）。PI 3 K β与MAP 4的相互作用控制PI 3 K β的表达。 与PI 3 K β活化、PI 3，4，5 P3生成和 Akt激活（9）。结合PI 3 K β的MAP 4的MTBD显示出与微管蛋白惊人的高同源性。 神经元微管相关蛋白tau和MAP 2的结合域，刺激了以下假设： tau和MAP 2替代MAP 4控制神经元中的PI 3 K/Akt存活信号传导。我们的初步数据显示 在原代神经元、诱导多能干细胞衍生的神经元和 神经元细胞系。siRNA介导的tau敲低阻断了胰岛素刺激的Akt活化。 我们假设tau蛋白支架使PI 3 K沿着轴突和树突中的微管移动，以控制生长因子 刺激神经元的PI 3 K/Akt存活信号。tau蛋白过度磷酸化及其聚集增加 在阿尔茨海默病的发展过程中， 在生长因子刺激的PI 3 K/Akt信号传导的损失中，PI 3 K/Akt信号传导对神经元细胞存活和功能至关重要。 建议研究的重点是建立和理解tau蛋白在PI 3 K/Akt信号转导中的作用机制 并定义tau蛋白中的PI 3 K β相互作用位点。PI 3 K β和tau之间的相互作用将用于定义 在tau的MTBD中的PI 3 K相互作用位点，并研究这些位点是否与致病突变体一致 以及tau蛋白MTBD中的过度磷酸化位点。我们将定义tau损失对空间分布的影响， PI 3 K β与轴突和树突中活化受体的共定位和相互作用，以及对生长的影响 因子刺激PI 3，4，5 P3产生和Akt激活。这将通过一个系统的 研究表达对PI 3 K β结合缺陷的突变tau蛋白的影响， 细胞渗透性肽对空间PI 3 K/Akt信号传导和神经元存活的PI 3 K β-tau相互作用。