Emerging Roles of Higher-order Polyamines During Tauopathies

包括阿尔茨海默病（AD）在内的Tau蛋白病影响了近600万美国人， 2000亿美元用于医疗保健。它们伤害家庭，使受害者失去记忆、尊严， 最后，他们的身份。目前不存在用于治疗Tau蛋白病和AD的疾病修饰剂， 自发恢复是未知的; tau蛋白病的诊断是死刑判决。拟议战略， 减少tau负荷包括增加清除，减少磷酸化或硝化，减少聚集， 和消炎等。精氨酸代谢处于一个关键的分支点， 作为由一氧化氮合酶产生一氧化氮或由 精氨酸酶（Arg 1）。我们的数据表明，在tau蛋白病小鼠模型中Arg 1过表达减少了多个 tau表型方面;磷酸化tau沉积，Gallyas染色，海马萎缩，高分子 加权tau多聚体、tau硝化、炎症的细胞因子标志物、自噬抑制剂和蛋白质 激酶活化这些效应中的许多也可以在细胞培养中证明。我们还发现，高- 有序多胺直接阻断tau聚集并促进生理条件下溶液中微管组装 浓度，但乙酰化多胺未能模仿这种影响。这种操作的几个明显效果 可以介导Arg 1过度表达和多胺代谢的这些显著益处。这个目标 应用是为了更好地理解多胺如何有助于减少tau表型的益处， 并确定治疗tau蛋白病和可能的AD的其他潜在靶点。利用基因治疗，小鼠 tau蛋白病模型和敲除模型，我们将测试四个目标。1)确定多胺是否增加 减少Tau病理学。2)确定是否减少多胺增强Tau病理。3)测试是否 多胺的药理学营养调节调节Tau病理学和4）测试多胺的缺失是否 SSAT降低Tau病理学。这些目标的成功将增加我们对以下方面作用的认识： 多胺代谢调节tau表型。我们的目标是确定更多的治疗靶点 这可以通过药理学试剂来调节，以阻止或减缓tau沉积的进展， 患有神经退行性疾病的人

Collectively tauopathies including Alzheimer’s disease (AD) impact close to 6 million Americans and cost over $200 billion in medical care. They devastate families and cause victims to lose their memory, their dignity and, finally, their identity. Currently no disease modify agents exist for treating tauopathies, and AD and spontaneous recovery is unknown; a diagnosis of tauopathy is a death sentence. Strategies proposed to reduce tau burden include increasing clearance, decreasing phosphorylation or nitration, reducing aggregation, and diminishing inflammation, among others. Arginine metabolism is poised at a critical branch-point and serves as a precursor for nitric oxide generation from nitric oxide synthases or polyamine production from arginase (Arg1). Our data indicates that Arg1 overexpression in a mouse model of tauopathy reduces multiple aspects of the tau phenotype; phospho-tau deposition, Gallyas staining, hippocampal atrophy, high molecular weight tau multimers, tau nitration, cytokine markers of inflammation, inhibitors of autophagy, and protein kinase activation. Many of these effects can also be demonstrated in cell culture. We also show that higher- order polyamines directly block tau aggregation and promote microtubule assembly in solution at physiological concentrations, but acetylated polyamines fail to mimic this affect. Several distinct effects of this manipulation could mediate these remarkable benefits of Arg1 over expression and polyamine metabolism. The goal of this application is to better understand how polyamines contribute to the benefits of reducing the tau phenotype, and identify other potential targets for treating tauopathies and possibly AD. Utilizing gene therapy, mouse models of tauopathy, and knockout models we will test four aims. 1) Determine if Increased Polyamines Diminish Tau Pathology. 2) Determine if Reduced Polyamines Enhance Tau Pathology. 3) Test if Pharmacological Nutritional Modulation of Polyamines Regulates Tau Pathology and 4) Test if the Deletion of SSAT Reduces Tau Pathology. Success in these aims will increase our knowledge regarding the role of polyamines metabolism in regulating the tau phenotype. Our goal is to identify additional therapeutic targets that could be regulated by pharmacological agents to arrest or slow the progression of the tau deposition in humans with neurodegenerative disease.