Functional Roles of Nurr1 in AD Related Pathophysiology

 描述(申请人提供)：阿尔茨海默病(AD)，最常见的神经退行性疾病，影响全球超过3500万患者(美国为500万)。随着人口老龄化，患有阿尔茨海默病的人数和我们社会的负担将会升级；美国国会最近的一份报告估计，到2050年，联邦在AD上的支出将增加到每年超过1万亿美元(按今天的美元计算)(国家阿尔茨海默氏症战略计划：阿尔茨海默氏症研究小组的报告，2009年；：//www.alz.org/documents/national/report_asg_alzplan.pdf).由于没有治疗方法可以延缓或阻止疾病的进程，因此寻找新的途径和介质来关键地调节AD的病理生理学具有至关重要的意义。孤儿核受体Nurr1对中脑多巴胺神经元的发育和维持以及对炎症诱导的细胞死亡的保护起着至关重要的作用。然而，它在阿尔茨海默病(AD)相关发病机制中的作用还完全不清楚。尽管Nurr1被认为是一种非配体依赖的活性转录因子，但我们最近发现了一些小分子(如阿莫地喹(AQ)和氯喹(CQ))，它们通过与其配体结合结构域(LBD)直接相互作用来显著调节Nurr1‘S的转录功能，这表明Nurr1’S的活性可以受到激动剂/合成配体的调节。此外，使用我们的Nurr1特异性抗体，我们发现Nurr1在海马结构和额叶皮质显著表达，并且在有效的AD动物模型5XFAD小鼠中，Nurr1表达的细胞数量显著减少，并伴随着斑块沉积的增加。此外，我们还发现，与年龄匹配的健康对照组相比，在AD死后脑中，Nurr1在海马区的表达显著降低，提示Nurr1可能在AD的病理生理过程中具有功能作用。基于这些发现，这一建议将解决我们的假设，即Nurr1在AD相关的病理生理学中发挥关键作用，并且其激动剂(S)激活Nurr1为AD提供了一种新的治疗方法。如果这个项目的目标成功实现，它将通过证明Nurr1是一个关键的介体和治疗开发的有效靶点，从而引发AD研究的新方向。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common neurodegenerative disease, affects more than 35 million patients worldwide (>5 million in US). With an aging population, the number of people suffering from AD and the burden on our society will escalate; a recent report by the US Congress estimates that federal spending on AD will increase to over $1 trillion (in today's dollars) per year by 2050 (A National Alzheimer's Strategic Plan: The report of the Alzheimer's study group, 2009; ://www.alz.org/documents/national/report_asg_alzplan.pdf). Since there is no therapy that can slow down or halt the disease process, it is of paramount significance to identify novel pathways and mediators that critically regulate the pathophysiology of AD. The orphan nuclear receptor Nurr1 play a critical role for development and maintenance of midbrain dopamine neurons as well as their protection from inflammation-induced cell death. However, its role in Alzheimer's disease (AD)-related pathogenesis is completely unknown. Although Nurr1 is considered to be a ligand-independent and constitutively active transcription factor, we recently identified small molecules (e.g., amodiaquine (AQ) and chloroquine (CQ)) that prominently modulate Nurr1's transcriptional function via direct interaction with its ligand-binding domain (LBD), suggesting that Nurr1's activity can be modulated by agonists/synthetic ligands. Furthermore, using our Nurr1-specific antibodies, we found that Nurr1 is prominently expressed in the hippocampal formation and frontal cortex and that the number of Nurr1-expressing cells significantly declines in the 5XFAD mouse, a valid animal model of AD, in an age-dependent manner, accompanied with increased plaque deposition. In addition, we found that Nurr1 expression is significantly reduced in the hippocampus of AD postmortem brain, compared with age-matched healthy control brain, suggesting that Nurr1 may have functional roles related to AD pathophysiology. Based on these findings, this proposal will address our hypothesis that Nurr1 plays critical roles in AD-related pathophysiology and that Nurr1 activation by its agonist(s) provides a novel therapeutic approach for AD. If goals of this project are successfully achieved, it will spark a new direction of AD research by demonstrating that Nurr1 is a key mediator and a valid target for therapeutic development.