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

项目总结 包括阿尔茨海默病在内的tau病理是最常见和最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)，但目前还没有治疗这种疾病的治疗药物 疾病，除了最近批准的一种有争议的药物(7)。通过细胞内神经原纤维的形成 皮层和海马区过度磷酸化的tau蛋白的缠结(NFT)是一个关键 Tau病理的病理特征，即过度磷酸化tau如何影响的确切机制 神经元中缺乏生存信号。最近我们发现PI3K/Akt生存信号 通路由直接相互作用的非神经元型微管相关蛋白4(MAP4)控制 与PI3K通过其微管结合域(MTBD)结合(9)。PI3K与MAP4的相互作用控制PI3K 与PI3K激活、PI3、4、5P3生成所需的激活受体激酶的关联 AKT激活(9例)。与PI3K结合的MAP4的MTBD与微管有很高的同源性- 神经元微管相关蛋白tau和MAP2的结合域，刺激了以下假设 Tau和MAP2替代MAP4控制神经元中的PI3K/Akt生存信号。我们的初步数据显示 Tau和PI3K在原代神经元、诱导的多能干细胞来源的神经元中的联系，以及 一种神经细胞系。SiRNA介导的tau基因敲除阻断了胰岛素刺激Akt的激活。 我们假设tau是沿着轴突和树突中的微管将pi3k作为支架来控制生长因子的。 刺激神经元PI3K/Akt存活信号。Tau蛋白过度磷酸化及其聚集增加 在阿尔茨海默病期间，进展损害了PI3K沿微管的空间组织，导致 在缺失生长因子的刺激下，PI3K/Akt信号通路对神经细胞的生存和功能至关重要。 建议的研究重点是从机制上建立和理解tau在PI3K/Akt信号转导中的作用 并定义了tau中的pi3k相互作用位点。PI3K和Tau之间的相互作用将被用来定义 PI3K在tau病中的相互作用位点及其与致病突变的关系 和tau基因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， PI3K与激活受体在轴突和树突中的共存、相互作用及其对生长的影响 因子刺激PI3、4、5P3的产生和Akt的激活。这一点将通过系统性的 表达缺失tau基因对PI3K结合的影响及对PI3K DNA结合的破坏作用 细胞通透性多肽对PI3K/信号转导和神经元存活的影响

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.