Molecular Mechanisms Underlying Obesity-related Memory Deficits

项目摘要/摘要 在理解中枢神经系统潜在的分子机制方面存在着根本的差距。 (中枢神经系统)胰岛素转运。由于中枢神经系统胰岛素在记忆中的重要性，这代表着一个重要的差距。 长期目标是了解肥胖对正常和病理性脑老化的影响。这个 本研究旨在探讨高脂饮食(HFD)诱导肥胖对中枢神经系统的影响。 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会使大脑 易受记忆力损害的。中心假设是HFD减少了海马体内胰岛素的转运， 从而损害认知功能。这一假设是基于申请人的 实验室。这项拟议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 功能将为开发减轻肥胖相关的创新方法奠定基础 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：HFD 减少海马区胰岛素转运和2)检验假设，即中枢胰岛素转运受损会导致 认知缺陷。在目标1下，将利用在HFD小鼠身上的分子技术来评估对 胰岛素进入海马体。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的海马微血管中进行评估。在第二个下面 目的：一种血管内皮细胞特异性胰岛素受体缺失的转基因小鼠将用于 评价胰岛素受体在中枢神经系统胰岛素转运中的作用及其对认知功能的影响。这个 方法是创新的，因为它利用了专门设计的动物模型来理解 肥胖相关中枢胰岛素转运障碍的机制及其对认知功能的影响 功能。这项拟议的研究具有重要意义，因为预计它将导致 有针对性的治疗以延缓或防止认知能力下降。最终，这项工作的结果也可能是 有助于改善与神经障碍相关的认知功能，如轻度认知障碍 或者阿尔茨海默氏症。

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.