Does E4orf1 prevent further deterioration in Alzheimer's disease pathology in older mice

项目摘要/摘要 阿尔茨海默病(AD)是一种神经退行性疾病，伴随着认知能力下降，痴呆 以及最终的死亡。我们对阿尔茨海默病神经病理学的理解有了很大的进步， 然而，没有治疗策略可以持续地缓解认知症状或预防、治愈或 减缓它的进程。有趣的是，一些精心设计的流行病学研究已经建立了 在2型糖尿病(T2D)和AD之间，T2D是一种慢性、与年龄相关的退行性疾病，认为T2D是一种 发展全因痴呆的危险因素以及可归因于阿尔茨海默病的痴呆。T2D和AD，以及其他 神经系统疾病有几个共同的临床和生化特征。其中尤为重要的是 是胰岛素信号受损，提示致病机制重叠。因此，一个有效的治疗方法 针对一种疾病的策略可能对另一种疾病具有潜在价值。几项临床和基础科学研究已经 表明抗糖尿病药物可以改善认知功能。尽管有希望，但这些策略都不是 提高了我们的理解或有效的治疗选择。我们的长期目标是剖析 T2D和AD之间共同的机制调节AD进展中的分子途径。这些 这些发现将有助于发现有效的治疗策略来预防AD或其进展。上一首 治疗策略要么作用于外周，要么直接作用于大脑，这就提出了外周是否也起作用的问题 因为影响阿尔茨海默病需要以中枢血糖控制为目标。因此，中心假设是 外周高胰岛素血症导致大脑胰岛素抵抗和认知功能下降，并缓解 外周和大脑区域的高胰岛素血症将减少与AD相关的分子恶化。这个 这项探索性拨款的总体目标是利用腺病毒蛋白E4orf1降低 外周和中枢高胰岛素血症和高血糖可延缓AD进展。理由是 恢复正常的胰岛素作用和防止认知功能下降的进一步损害将有助于识别 提供新的治疗机会的机制。使用腺病毒的内源性胰岛素节约作用 蛋白E4orf1，AIMS将阐明一种以前未知的有效治疗方法 公元一代的。这是与以前用于AD治疗的抗糖尿病方法的范式转变，并将有助于 修改目前可用的治疗方法或确定预防和更好的临床管理的新选择 广告。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD), is a neurodegenerative disease with associated cognitive decline, dementia and eventual death. There has been significant advancement in our understanding of AD neuropathology, however, there are no therapeutic strategies that consistently relieve cognitive symptoms or prevent, cure or slow its progression. Interestingly, a number of well-designed epidemiological studies have established a link between Type 2 Diabetes (T2D), a chronic, age-related degenerative disorder and AD, identifying T2D as a risk factor for developing all cause dementia and dementia attributable to AD. T2D and AD, together with other neurological conditions, share several clinical and biochemical features. Particularly important amongst these is impaired insulin signaling, suggesting overlapping pathogenic mechanisms. Hence, an effective treatment strategy in one disease could have potential value in the other. Several clinical and basic science studies have shown that anti-diabetic medications can improve cognitive function. Despite promise, none of these strategies have resulted in improving our understanding or effective treatment options. The long-term goal is to dissect shared mechanisms between T2D and AD regulating the molecular pathways in AD progression. These discoveries will facilitate discover effective treatment strategies to prevent AD or its progression. Previous treatment strategies either act in the periphery or directly in the brain, raising the question if peripheral as well as central glycemic control needs to be targeted for influencing AD. Therefore, the central hypothesis is that peripheral hyperinsulinemia contributes to brain insulin resistance and cognitive decline, and that alleviating hyperinsulinemia in both periphery and brain regions will reduce AD-related molecular deterioration. The overall objective of this exploratory grant is to harness the ability of adenoviral protein E4orf1 to reduce peripheral and central hyperinsulinemia and hyperglycemia to attenuate AD progression. The rationale is that restoring normal insulin action and prevention of further impairment in cognition decline will help identify mechanisms to offer new therapeutic opportunities. Using the endogenous insulin sparing action of adenoviral protein E4orf1, the aims will elucidate a previously unidentified therapeutic approach for the effective treatment of AD. This is a paradigm shift from previously used anti-diabetic approaches for AD treatment and will help modify currently available therapies or identify new options for prevention and better clinical management of AD.