Mechanisms and use of antidiabetic agents in brain aging and Alzheimer's disease

描述（由申请人提供）：阿尔茨海默病（AD）是美国仅次于心脏病和癌症的第三大最昂贵的疾病，最近发病率有所增加，从第7位上升到第5位，成为老年人的主要死因。目前可用的医学策略治疗症状，而不是解决导致AD患者认知功能进行性下降的潜在过程。然而，临床和基础科学研究的结果表明，抗糖尿病药物（例如，噻唑烷二酮-TZD）在治疗AD中可能是有益的，并且一些人类和动物研究已经表明，使用罗格列酮（TZD）可以改善记忆并导致认知改善。这些结果似乎提供了令人信服的初步证据，支持使用抗糖尿病药物来对抗与AD相关的认知障碍。然而，关于TZDs的潜在分子机制或CNS靶点的身份知之甚少。TZD的一些建议的有益作用包括重建胰岛素敏感性和相关的外周和/或CNS葡萄糖利用，沿着炎性细胞因子、Ab 1 -42沉积、小胶质细胞活化和细胞内Ca 2+水平的降低。鉴于钙离子失调被认为是脑老化和AD的标志，也存在于糖尿病动物模型中，我们建议脑老化的一些钙离子生物标志物可能是TZDs干预的靶点。使用电生理学，分子和钙离子成像技术沿着与一组合格的科学家，该项目将测试的整体假设，一些TZD可以改善老年动物的认知状态，通过减少大脑老化和海马神经退行性变的关键生物标志物。我们将通过以下特定目的确定TZD治疗AD的潜在用途的分子基础：1）检验TZD通过使神经元和/或神经胶质细胞内的Ca 2+水平正常化而作为神经保护剂的假设;和2）检验体内TZD治疗可以改善老年动物的认知并恢复Ca 2+稳态的预测。我们的研究结果可能为TZD在预防/延缓AD认知功能下降方面的治疗应用提供支持。此外，这些研究将有助于未来的药物发现工作，以产生新的TZD衍生或类似的药物用于治疗AD。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the third most costly disease in the United States after cardiac disease and cancer, has shown an increase in incidence recently, moving from 7th to 5th as a leading cause of death among the elderly. Currently available medical strategies treat the symptoms rather than address the underlying processes responsible for the progressive decline in cognitive function seen in AD patients. However, results from both clinical and basic science research suggest that antidiabetic agents (e.g., thiazolidinediones - TZDs) may be beneficial in the treatment of AD, and a few human and animal studies have shown that use of rosiglitazone (a TZD) can improve memory and lead to cognitive improvements. These results appear to provide compelling preliminary evidence to support the use of antidiabetic drugs to combat the cognitive impairment associated with AD. However, little is known about the underlying molecular mechanisms, or about the identity of the CNS targets of TZDs. Some of the proposed beneficial effects of TZDs include reestablishment of insulin sensitivity and associated peripheral and/or CNS glucose utilization, along with reductions in inflammatory cytokines, Ab1-42 deposits, microglial activation, and intracellular Ca2+ levels. Given that Ca2+ dysregulation is considered a hallmark of brain aging and AD, and is also present in animal models of diabetes, we propose that some Ca2+ biomarkers of brain aging may be targets for intervention with TZDs. Using electrophysiological, molecular and Ca2+ imaging techniques along with a team of qualified scientists, this project will test the overall hypothesis that some TZDs can improve cognitive status in aged animals, by reducing key biomarkers of brain aging and neurodegeneration in the hippocampus. We will determine the molecular bases underlying the potential use of TZDs for the treatment of AD by the following Specific Aims: 1) to test the hypothesis that TZDs act as neuroprotective agents by normalizing Ca2+ levels within neurons and/or glial cells; and 2) to test the prediction that in vivo TZD treatment can improve cognition in aged animals and restore Ca2+ homeostasis. Results form our studies may provide support for the therapeutic application of TZDs in preventing/retarding the cognitive decline seen in AD. Furthermore, these studies will contribute to future drug discovery efforts to generate new TZD-derived or similar drugs for the treatment of AD.