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

描述(由申请人提供)：代谢障碍，特别是2型糖尿病(T2D)，在当代生活方式中很常见，发病率也在增加。T2D与不良的健康后果有关，包括大脑受损。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系统存在相互作用，特别是强烈影响胰岛素敏感性的脂肪因子(如脂联素和瘦素)。确定增加胰岛素抵抗患者AD风险的分子机制现在具有重大的科学意义(PAS-11-029)，它们的阐明可能导致新的治疗策略。胰岛素抵抗是T2D的一个核心特征，可能会导致脑部病理增加。T2D与脑血管疾病的关系不大，但也许更令人感兴趣的是，最近的数据显示，脑胰岛素信号异常与AD病理有关，特别是淀粉样蛋白和tau相关的病理。此外，AD还发现脂肪因子受体表达异常。提出的跨学科协作项目的总体目标是在人脑中建立连接胰岛素、多巴连结素和瘦素信号的分子机制，并确定这个网络中的失调与大脑结构、病理和功能(包括阿尔茨海默病和认知障碍)的关系。这项拟议的研究将量化胰岛素、脂联素和瘦素信号、神经元和突触的标记物，并使用200名居住在社区的女性和男性的现有病理和临床数据，他们患有和不患有T2D，涉及一系列认知功能，他们的临床特征很好，作为宗教教派研究的参与者死亡和尸检(P30AG010161；R01AG015819)。首先，我们将描述患有和不患有T2D的受试者脑中胰岛素、脂联素和瘦素途径成分的表达水平(目标1)。然后，在人类死后组织中使用一种新的体外刺激范例，我们将在实验中测试胰岛素和脂肪因子信号在脑组织中的刺激反应和相互作用(目标2)。最后，在研究的临床病理翻译部分，我们将测试胰岛素、脂联素和瘦素信号与脑结构(突触标志物)、病理(淀粉样蛋白和tau蛋白)和功能(认知)的关系。由于胰岛素抵抗是一种常见的疾病，有治疗方法可用，这项研究将在研究胰岛素和脂肪因子在人脑中的机制方面开辟新的天地，并表明胰岛素抵抗和脂肪因子功能障碍与人脑的变化在多个水平上相关，从而为改善公众健康提供重要数据。

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.