Molecular Mechanisms Underlying Obesity-related Memory Deficits

项目总结/摘要 在理解中枢神经系统的分子机制方面存在着根本性的空白 (CNS)胰岛素转运由于CNS胰岛素在记忆中的重要性，这代表了一个重要的差距。 长期目标是了解肥胖对正常和病理性大脑衰老的影响。的 该特定应用的目的是研究高脂饮食（HFD）诱导的肥胖对CNS的影响 胰岛素和认知功能。肥胖对中枢神经系统胰岛素转运的影响可能使大脑 易受记忆损伤的影响。中心假设是HFD减少海马胰岛素转运， 从而损害认知功能。这一假设是基于申请人的初步数据。 实验室这项研究的基本原理是，了解中枢神经系统胰岛素对大脑的影响， 该职能将为开发创新方法以减轻肥胖相关疾病奠定基础。 认知能力下降因此，这一假设将通过追求两个具体目标来检验：1）检验假设，即HFD 减少海马胰岛素转运和2）测试假设，损害中枢神经系统胰岛素转运导致 认知缺陷在目标1下，将利用HFD小鼠中的分子技术来评估 注入海马体此外，胰岛素受体表达和信号蛋白的变化将 在代表血脑屏障的分离海马微血管中进行评价。根据第二个 目的是利用血管内皮细胞特异性缺乏胰岛素受体的转基因小鼠， 评价胰岛素受体在CNS胰岛素转运中的作用以及对认知功能的影响。的 这种方法是创新的，因为它利用了一种专门设计的动物模型来了解 肥胖相关中枢神经系统胰岛素转运障碍的机制及其对认知功能的影响 功能拟议的研究是重要的，因为预计它有望导致发展 有针对性的治疗来延缓或预防认知能力下降。最终，这项工作的结果也可能是 可用于改善与神经障碍如轻度认知障碍相关的认知功能 或阿尔茨海默病。

Project Summary/Abstract There is a fundamental gap in understanding the molecular mechanisms underlying central nervous system (CNS) insulin transport. This represents an important gap due to the importance of CNS insulin in memory. The long-term goal is to understand the impact of obesity on both normal and pathological brain aging. The objective of this particular application is to investigate the effect of high-fat diet (HFD) induced obesity on CNS insulin and cognitive function. Obesity-induced effects on CNS insulin transport may render the brain susceptible to memory impairment. The central hypothesis is that HFD reduces hippocampal insulin transport, thereby impairing cognitive function. This hypothesis is based on preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that understanding the impact of CNS insulin on brain function will set the stage for the development of innovative approaches to mitigate obesity-associated cognitive decline. Thus, this hypothesis will be tested by pursing two specific aims: 1) test hypothesis that HFD reduces hippocampal insulin transport and 2) test hypothesis that impairing CNS insulin transport results in cognitive deficits. Under Aim 1, molecular techniques in HFD mice will be utilized to evaluate the uptake of insulin into the hippocampus. In addition, the changes in insulin receptor expression and signaling proteins will be evaluated in isolated hippocampal microvessels, which represent the blood brain barrier. Under the second aim, a transgenic mouse lacking the insulin receptor specifically in vascular endothelial cells will be used to evaluate the role of the insulin receptor in CNS insulin transport and the impact on cognitive function. The approach is innovative, because it utilizes an animal model specifically designed to understand the mechanisms underlying obesity-related impairments in CNS insulin transport and its impact on cognitive function. The proposed research is significant, because it is expected it is expected to lead to the development of targeted therapies to delay or prevent cognitive decline. Ultimately, the results of this work may also be useful in improving cognitive function associated with neurological disorders such as Mild Cognitive Impairment or Alzheimer's disease.