Mechanisms linking insulin resistance to brain structure, pathology, and function

描述（由申请方提供）：代谢紊乱，尤其是2型糖尿病（T2 D），在现代生活方式中很常见，且发病率不断增加。T2 D与不利的健康后果相关，包括受损的大脑。然而，大脑中胰岛素抵抗的原因和影响是复杂的，因为与其他激素信号传导系统，特别是脂肪因子（例如，脂联素和瘦素），其强烈影响胰岛素敏感性。表征增加胰岛素抵抗患者AD风险的分子机制现在具有很大的科学意义（PAS-11-029），其阐明可能导致新的治疗策略。胰岛素抵抗是T2 D的核心特征，可能导致脑病理学增加。T2 D与脑血管疾病适度相关，但可能更令人感兴趣的是，最近的数据显示脑胰岛素信号传导异常与AD病理学相关，特别是淀粉样蛋白-β和tau相关的病理学。此外，在AD中也发现了脂肪因子受体表达异常。拟议的跨学科合作项目的总体目标是建立连接人脑中胰岛素，adopinectin和瘦素信号传导的分子机制，并确定该网络中的失调如何与大脑结构，病理学和功能相关，包括AD和认知障碍。拟议的研究将量化胰岛素、脂联素和瘦素信号传导、神经元和突触的标志物，并使用来自200名社区居民女性和男性的现有病理和临床数据，这些女性和男性患有或不患有T2 D，并且跨越认知功能谱，这些患者在临床上具有良好的特征，并且作为宗教秩序研究的参与者死亡并进行尸检（P30AG010161; R01AG015819）。首先，我们将描述脑胰岛素，脂联素和瘦素途径成分的表达水平在受试者和没有T2 D（目的1）。然后，在人类死后组织中使用新的离体刺激范例，我们将实验性地测试脑组织中胰岛素和脂肪因子信号传导的刺激反应和相互作用（目的2）。最后，在本研究的临床病理转化部分，我们将测试胰岛素、脂联素和lepti信号传导与脑结构（突触标记物）、病理学（淀粉样蛋白-β和tau）和功能（认知）的关系。由于胰岛素抵抗是一种常见的疾病，治疗方法是可行的，这项研究将在人类大脑中胰岛素和脂肪因子机制的研究中开辟新的领域，并显示胰岛素抵抗和脂肪因子功能障碍与人类大脑的多个水平的变化有关，从而为改善公共健康提供重要数据。

DESCRIPTION (provided by applicant): Metabolic disturbances in particular type 2 diabetes mellitus (T2D), are common and increasing in incidence with contemporary lifestyles. T2D is associated with adverse health consequences, including impaired brain Yet, the causes and effects of insulin resistance in the brain are complex, as there are reciprocal interactions with other hormone signaling systems, in particular the adipokines (e.g., adiponectin and leptin) which strongly affect insulin sensitivity. Characterizing the molecular mechanisms that increase risk of AD for persons with insulin resistance is now of great scientific interest (PAS-11-029) and their elucidation may lead to novel therapeutic strategies. Insulin resistance, a core feature of T2D, may lead to increased brain pathology. T2D is modestly associated with cerebrovascular disease, but perhaps of even greater interest, recent data show brain insulin signaling abnormalities associated with AD pathology, specifically amyloid-ß and tau-related pathology as well. Furthermore, adipokine receptor expression abnormalities have also been found in AD. The overall goal of the proposed interdisciplinary collaborative project is to establish molecular mechanisms linking insulin, adopinectin, and leptin signaling in human brain, and determine how dysregulation in this network is associated with brain structure, pathology, and function, including AD and cognitive impairment. The proposed study will quantify markers of insulin, adiponectin, and leptin signaling, neurons and synapses, and use existing pathologic and clinical data from 200 community-dwelling women and men, with and without T2D and across a spectrum of cognitive function, who were well-characterized clinically and died and came to autopsy as participants in the Religious Orders Study (P30AG010161; R01AG015819). First, we will describe expression levels of brain insulin, adiponectin, and leptin pathway components in subjects with and without T2D (Aim 1). Then, using a novel ex-vivo stimulation paradigm in human postmortem tissue, we will experimentally test the stimulated responses and interactions of insulin and adipokine signaling in brain tissue (Aim 2). Finally, in the clinicopathologic translational component of the study, we will test the relations of insulin, adiponectin, and lepti signaling to brain structure (synaptic markers), pathology (amyloid-ß and tau), and function (cognition). Because insulin resistance is a common condition for which therapies are available, this study will break new ground in research of insulin and adipokine mechanisms in human brain, and show insulin resistance and adipokine dysfunction are associated with changes in the human brain at multiple levels, thus providing important data with potential to improve public health.