Determining if Reduced Insulin Response in the Brain is Linked to Cognitive Loss

项目摘要 随着人们年龄的增长，他们患痴呆症的风险会增加。对于II型患者来说，这种风险会增加。 糖尿病。事实上，患有II型糖尿病的人患痴呆症的可能性也是前者的两倍以上。 通过阿尔茨海默病(AD)、血管认知障碍(CVI)或痴呆的发展 将军。对AD患者大脑的检查也揭示了这种相关性，因为大多数AD患者的大脑 在海马区显示胰岛素抵抗，即使在没有临床诊断的患者中也是如此 II型糖尿病。这种大脑形式的胰岛素抵抗被称为III型糖尿病。 在以前的研究中，我们利用已知的功能丧失来检查早老素活性降低的效果。 果蝇早老素(PSN)基因突变我们发现PSN活性降低的果蝇(PSN-HETS)表现出 在经典求爱学习和记忆范式中，年龄起病的学习和记忆丧失。在更近的时间 对PSN-HET大脑的研究发现，随着年龄的增长，他们会出现脑内胰岛素抵抗。我们发现 当PSN-HET果蝇在幼年(成年第5天)表现出正常认知时，它们的大脑显示 增加胰岛素信号，增加对胰岛素刺激的敏感性。陈旧的PSN-HET大脑(第30天 成年期)，表现为学习和记忆丧失，对胰岛素刺激没有反应。我们假设 老年多发性硬化症患者脑内胰岛素抵抗的建立导致认知障碍 通过这种模式。在这项建议的第一个目标中，我们将确定PSN突变是否与家族性阿尔茨海默病有关 疾病(FAD)也会导致大脑中胰岛素信号的改变，大脑中的胰岛素抵抗和年龄的发病 认知能力丧失。然后我们将探索大脑中胰岛素信号的减少是否可以挽救 大脑胰岛素抵抗和认知丧失。在本提案的第二个目标中，我们将确定PSN 突变会导致外周胰岛素信号的改变和外周胰岛素抵抗。这些研究将 确定PSN活性的丧失或改变是否优先导致大脑中的胰岛素抵抗。我们还将 测试已知的诱导果蝇外周胰岛素抵抗的治疗是否也会导致 大脑胰岛素抵抗和认知缺陷。这些研究将在对照苍蝇、PSN-HET和 FAD突变杂合子的果蝇，允许检查饮食和减少的PSN的相互作用 活动。这些研究将探索PSN活性降低或改变对胰岛素信号转导的作用。 以及在大脑中建立胰岛素抵抗以及这是否会导致认知障碍。 这些研究也将为探索由于脑胰岛素的发展而导致的痴呆症提供一个有用的模型。 总体上是抵抗的。

Project Summary As people age, their risk for developing dementia increases. This risk is enhanced for those with type II diabetes. In fact, individuals with type II diabetes are more than twice as likely to suffer from dementia, either through the development of Alzheimers disease (AD), Vascular cognitive impairment (CVI) or dementia in general. Examination of brains from AD patients also reveals this correlation as most brains from AD patients display insulin resistance in the hippocampus, even in patients that have not been clinically diagnoses with type II diabetes. This brain form of insulin resistance is referred to as type III diabetes. In previous studies we examined the effect of reduced presenilin activity utilizing known loss of function mutations of Drosophila presenilin (psn). We found that flies with reduced psn activity (psn-hets) displayed an age-onset loss-of-learning and memory in the classic courtship learning and memory paradigm. In more recent studies of the psn-het brains we have found that they develop brain insulin resistance with age. We find that when the psn-het flies are young (day 5 of adulthood) and display normal cognition, their brains display increased insulin signaling and increased sensitivity to insulin stimulation. Old psn-het brains (day 30 of adulthood) that display loss of learning and memory fail to respond to insulin stimulation. We hypothesize that the establishment of insulin resistance in the brains of the old psn-hets causes the cognitive deficits displayed by this model. In the first aim of this proposal we will determine if psn mutations linked to familial Alzheimers disease (FAD) also lead to altered insulin signaling in the brain, brain insulin resistance and age onset cognitive loss. We will then explore if the reduction of insulin signaling in the brain can rescue the formation of brain insulin resistance and cognitive loss. In the second aim of this proposal we will determine if psn mutations lead to alterations in peripheral insulin signaling and peripheral insulin resistance. These studies will determine if loss or alteration of psn activity preferentially induce insulin resistance in the brain. We will also test if treatments that are known to induce the development of peripheral insulin resistance in flies also cause brain insulin-resistance and cognitive deficits. These studies will be performed with control flies, psn-hets and flies heterozygous for FAD mutations, allowing for an examination of the interaction of diet and reduced psn activity. These studies will explore the role that reduction of, or alteration in psn activity has on insulin signaling and the establishment of insulin resistance in the brain and whether this can cause cognitive impairment. These studies will also provide a useful model to explore the dementia due to the development of brain insulin resistance in general.