Early Events in Alzheimer Pathogenesis

 描述(申请人提供)：近20年来，我们的计划一直处于发现的前沿，解决由遗传因素(突变和其他等位基因)引起的神经元应激、创伤性脑损伤、癫痫样活动、血管紧张素、胰岛素/IGF1和自噬系统的破坏以及正常衰老所引发的神经炎症的后果。对神经发病机制中的关键早期事件和易感因素的了解，加上新的合作机会，现在将使该计划翻开新的一页，开始新的翻译研究。我们已经证明神经炎--尤其是白介素1(IL-1)的升高--是病理相关蛋白过度表达的主要驱动因素。例如，在患有唐氏综合症、癫痫、艾滋病毒感染、阿尔茨海默氏症和帕金森氏症的人类中，以及在啮齿动物模型和神经培养中，神经元应激导致APP和SAPP过度表达，从而诱导神经胶质细胞激活和IL-1。Aβ和其他容易聚集的蛋白质(例如α-突触核蛋白和过度磷酸化的tau)的产生也是如此。这些蛋白质扰乱或压倒泛素-蛋白酶体系统(UPS)，导致蛋白质病，包括运动蛋白和UPS元件的聚集。在项目3中，我们已经开始通过鉴定一种新的蛋白质来表征这种蛋白质病，这种蛋白质对β转基因线虫(线虫)中与年龄相关的UPS成分聚集至关重要，这种现象可以被非类固醇抗炎药和其他新药根除。这是额外的相关性，项目-1发现，α-突触核蛋白，过度磷酸化的tau，和Parkin(这两种蛋白质的E3泛素连接酶)在AD和PD中共同聚集。在项目2中发现的胰岛素抵抗和对新陈代谢的相关影响可能与这种蛋白质病及其炎性后遗症有关。我们认为，这三个因素--神经炎症、蛋白病变和胰岛素抵抗--相互引起和/或加强，导致神经退行性变，其特征是胶质细胞激活、IL-1过度表达和具有重叠成分的蛋白质聚集体，而与特定疾病分类无关。一个推论是，可以确定共同的靶点，从而开发出治疗药物，以减少疾病相关蛋白的聚集和神经系统疾病中的蛋白病变。拟议的研究旨在识别、探索和功能表征负责病理特征的特定路径，这些路径要么是一种疾病所特有的，要么是几种与年龄相关的神经疾病的共同特征。这样的描述可以确定适合于特定药物干预的可驯服的过程，并建议促进成功衰老的生活方式/环境条件。一项新的药物发现工作(核心D)的增加使我们能够测试压倒一切的假设，同时识别具有治疗潜力的先导化合物。因此，这个计划的弧线现在指向有效的治疗，基于在这里提出的和在整个该计划的生产历史中进行的机械性研究奠定的基础。

 DESCRIPTION (provided by applicant): For nearly 20 years, our Program has been at the leading edge of discoveries addressing the consequences of neuroinflammation triggered by neuronal stresses arising from genetic factors (mutation and other alleles), traumatic brain injury, epileptiform activity, corruption of angiotensin, insulin/IGF1 and autophagy systems, and normal aging. The resulting knowledge of key early events and predisposing factors in neuropathogenesis, together with new collaborative opportunities, now position this Program to turn the page and embark on novel translational studies. We have documented neuroinflammation-particularly elevation of interleukin 1 (IL-1) - to be a principal driver of overexpression of pathology-related proteins. For example, in humans with Down's syndrome, epilepsy, HIV infection, Alzheimer's, and Parkinson's, as well as in rodent models and neural cultures, neuronal stress leads to overexpression of APP and sAPP for induction of glial activation and IL-1. Production of Aβ and other proteins that are prone to aggregation (e.g., α-synuclein and hyperphosphorylated tau) follow suit. These proteins disrupt or overwhelm the ubiquitin-proteasome system (UPS) leading to proteinopathy that includes aggregation of motor proteins and elements of the UPS. In Project 3, we have begun to characterize this proteinopathy through identification of a novel protein that contributes critically to age-related aggregation of components of the UPS in Aβ-transgenic nematodes (C. elegans), a phenomenon eradicated by non-steroidal anti-inflammatory agents and other, and novel drugs. This is lent additional relevance by the Project-1 discovery that α-synuclein, hyperphosphorylated tau, and Parkin (the E3 ubiquitin ligase for these two proteins) co-aggregate in AD and PD. Insulin resistance and related effects on metabolism, uncovered in Project 2, are likely related to such proteinopathies and their inflammatory sequelae. We propose that these three elements-neuroinflammation, proteinopathy, and insulin resistance-cause and/or reinforce one another to create neurodegeneration that is characterized by glial activation, IL-1 overexpression, and protein aggregates with overlapping constituents regardless of the specific disease classification. A corollary is that common targets can be identified leadin to development of therapeutic drugs to reduce aggregation of disease-related proteins and proteinopathy in neurological diseases. The proposed studies are constructed to identify, explore, and functionally characterize specific pathways responsible for pathologic signatures that are either unique to one disease or are common to several age-related neurological diseases. Such delineation may identify tractable processes amenable to specific drug interventions and suggest lifestyle/environmental conditions that foster successful aging. The addition of a new drug-discovery effort (Core D) empowers us to test the over-riding hypothesis while simultaneously identifying lead compounds of therapeutic potential. Thus, the arc of this Program is now directed toward effective therapies, based on foundations laid through mechanistic research proposed here and conducted throughout the productive history of this Program.