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

抗糖尿病药物在脑衰老和阿尔茨海默病中的机制和用途

• 批准号: 7178775
• 负责人: Olivier Thibault
• 金额: $ 15.57万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178775
• 关键词: 2,4-thiazolidinedione; Action Potentials; Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antidiabetic Drugs; Basic Science; Biological Markers; Blood Vessels; Brain; Calcineurin; Cause of Death; Cell Survival; Clinical; Clinical Trials; Cognition; Cognitive; Condition; Cues; Cultured Cells; Deposition; Diabetes Mellitus; Diet; Disease; Elderly; Future; Glucose; Glutamates; Heart Diseases; Hippocampus (Brain); Homeostasis; Human; Image; Imaging Techniques; Impaired cognition; Inbred F344 Rats; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; International; Intervention; Laboratory Animals; Lead; Learning; Long-Term Potentiation; Malignant Neoplasms; Measures; Mediating; Medical; Memory; Mental Tests; Modeling; Molecular; Molecular Target; Monitor; Nature; Nerve Degeneration; Neuroglia; Neurons; Neuroprotective Agents; Outcome; Pathway interactions; Patients; Performance; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pioglitazone; Pliability; Population; Process; Property; Qualifying; Recruitment Activity; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Ryanodine Receptor Calcium Release Channel; Scientist; Slice; Source; Specificity; Streptozocin; Symptoms; Techniques; Testing; Therapeutic; Thiazolidinediones; Tissues; Toxic effect; United States; aged; aging brain; base; cell type; cellular targeting; cognitive function; cytokine; drug development; drug discovery; improved; in vivo; insight; insulin sensitivity; insulin sensitizing drugs; interdisciplinary approach; mature animal; mild neurocognitive impairment; morris water maze; neurotransmission; novel; novel therapeutics; prevent; programs; research study; rosiglitazone; symposium; synaptic function; young adult

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.

描述(申请人提供)：阿尔茨海默病(AD)是美国第三昂贵的疾病，仅次于心脏疾病和癌症，最近发病率有所上升，从第7位上升到第5位，成为老年人的主要死亡原因。目前可用的医学策略是治疗症状，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(如噻唑烷二酮-TZD)在治疗AD方面可能是有益的，一些人类和动物研究表明，使用罗格列酮(TZD)可以改善记忆和改善认知。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，对TZD的潜在分子机制或TZD的中枢神经系统靶标的身份知之甚少。TZDS的一些建议的有益效果包括重建胰岛素敏感性和相关的外周和/或中枢葡萄糖利用，以及炎性细胞因子、AB1-42沉积、小胶质细胞激活和细胞内钙水平的减少。鉴于钙离子失衡被认为是脑老化和AD的标志，也存在于糖尿病动物模型中，我们认为一些脑老化的生物标志物可能是TZDS干预的靶点。该项目将利用电生理、分子和钙离子成像技术，以及一组合格的科学家，测试一些TZD可以通过减少大脑老化和海马神经退化的关键生物标记物来改善老年动物认知状态的总体假设。我们将通过以下具体目标来确定TZDS治疗AD的潜在分子基础：1)验证TZDS通过调节神经元和/或神经胶质细胞内钙水平作为神经保护剂的假设；2)测试体内TZD治疗可以改善老年动物认知和恢复钙稳态的预测。我们的研究结果可能为TZDS在预防/延缓AD患者认知能力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努力，以产生新的TZD衍生或类似的药物用于治疗AD。