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

确定大脑中胰岛素反应降低是否与认知丧失有关

• 批准号: 9188283
• 负责人: THOMAS A JONGENS
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188283
• 关键词: Adult; Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Autopsy; Brain; Catalytic Domain; Cerebral cortex; Cleaved cell; Clinical Research; Cognition; Cognitive; Cognitive deficits; Complex; Courtship; Defect; Dementia; Development; Diabetes Mellitus; Diagnosis; Diet; Drosophila genus; Elderly; Genes; Genetic; Goals; Hippocampus (Brain); Human; Impaired cognition; Individual; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Investigation; Lead; Learning; Link; Maintenance; Memory; Memory Loss; Memory impairment; Metabolic; Modeling; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; PTEN gene; Pathway interactions; Patients; Peptide Hydrolases; Peripheral; Phosphatidylinositols; Phosphotransferases; Play; Reducing diet; Regulation; Risk; Risk Factors; Role; Short-Term Memory; Slice; Testing; Time; Training; Vascular Cognitive Impairment; age related; familial Alzheimer disease; fly; gene function; insulin signaling; loss of function; loss of function mutation; mind control; mutant; notch protein; novel therapeutic intervention; presenilin; prevent; receptor; receptor downregulation; receptor expression; response; secretase

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.

项目概要 随着人们年龄的增长，患痴呆症的风险也会增加。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是其两倍以上 阿尔茨海默病 (AD)、血管性认知障碍 (CVI) 或痴呆症的发展 一般的。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 即使在尚未被临床诊断为胰岛素抵抗的患者中，海马体也表现出胰岛素抵抗 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。 在之前的研究中，我们利用已知的功能丧失研究了早老素活性降低的影响 果蝇早老素（psn）的突变。我们发现 psn 活性降低的果蝇 (psn-hets) 表现出 经典求爱学习和记忆范式中年龄开始的学习和记忆丧失。在最近的 对 psn-het 大脑的研究发现，随着年龄的增长，它们会出现大脑胰岛素抵抗。我们发现 当 psn-het 果蝇还年轻（成年第 5 天）并表现出正常认知时，它们的大脑显示 增加胰岛素信号传导并增加对胰岛素刺激的敏感性。老 psn-het 大脑（第 30 天） 表现出学习和记忆丧失的成年期）无法对胰岛素刺激做出反应。我们假设 老 psn-hets 大脑中胰岛素抵抗的建立导致了认知缺陷 通过这个模型。在该提案的第一个目标中，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）还会导致大脑中胰岛素信号的改变、大脑胰岛素抵抗和年龄增长 认知丧失。然后我们将探讨大脑中胰岛素信号传导的减少是否可以挽救胰岛素的形成 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 是否 突变导致外周胰岛素信号传导和外周胰岛素抵抗的改变。这些研究将 确定 psn 活性的丧失或改变是否会优先诱导大脑中的胰岛素抵抗。我们还将 测试已知可诱导果蝇发生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。这些研究将使用对照果蝇、psn-hets 和 FAD 突变杂合果蝇，可用于检查饮食和 psn 减少的相互作用 活动。这些研究将探讨 psn 活性的减少或改变对胰岛素信号传导的作用 大脑中胰岛素抵抗的建立以及这是否会导致认知障碍。 这些研究还将提供一个有用的模型来探索由于脑胰岛素的发展而导致的痴呆症 抵抗力一般。