Adipose Tissue Amyloid Precursor Protein and Beta-Amyloid

描述(由申请人提供)：最近的流行病学研究表明，中年肥胖、2型糖尿病(T2 DM)和阿尔茨海默病(AD)的发展之间存在关联。淀粉样前体蛋白(APP)的改变处理导致神经元产生病理性淀粉样蛋白b(Ab)片段的增加，这是AD病理的主要组成部分。APP处理异常与胰岛素抵抗、高胰岛素血症、血脂异常和炎症有关，这些状态是肥胖和T2 DM的典型症状。脂肪组织是肥胖和2型糖尿病新陈代谢改变的主要部位。在肥胖时，它会慢性发炎，部分原因是T2 DM时脂肪组织的代谢功能发生了变化。我们最近报道，APP在人类脂肪组织细胞中表达，随着肥胖和T2 DM的增加而上调，并与胰岛素抵抗和炎症标志物相关。我们还发现，血浆抗体水平升高与脂肪细胞APP表达和胰岛素抵抗程度相关。根据这些数据，我们推测肥胖和T2 DM时脂肪组织APP和AB的改变可能是胰岛素抵抗状态与AD之间的联系机制。我们对这一假设的看法集中在与胰岛素抵抗状态相关的脂肪细胞和前脂肪细胞的变化是否会改变脂肪APP的调节和处理，并将在以下目标中进行测试：具体目标1：我们将测试脂肪组织细胞是否产生大量抗体，如果这种产生是循环抗体水平的决定因素，以及这一过程是否被肥胖、胰岛素抵抗和T2 DM改变。具体目标2：我们将测试胰岛素、葡萄糖和/或促炎因子是否直接调节脂肪组织细胞中APP或其加工酶的表达。具体目的3：确定单抗是否通过改变胰岛素受体信号通路和促炎途径影响脂肪组织细胞的葡萄糖摄取。这些目标中的每一个都将产生独立和新颖的数据，有助于理解脂肪APP和抗体在胰岛素抵抗状态中的作用，并可能为AD和T2 DM的治疗提供新的治疗靶点或预防策略。此外，该项目为申请者构成了一个严格的临床研究培训计划，整合了基础和临床研究，并提供了匹配的教学方法。 公共卫生相关性：最近的流行病学研究表明，肥胖和2型糖尿病等胰岛素抵抗状态与阿尔茨海默病的发生有关，这是一个发人深省的观察结果，因为肥胖和糖尿病是全球流行病。细胞生物学研究强烈支持这样的观点，即胰岛素抵抗会导致细胞变化促进阿尔茨海默病；我们的临床研究小组发现，淀粉样前体蛋白是阿尔茨海默病病理的主要成分，在脂肪组织中表达，随着肥胖而上调，并与胰岛素抵抗和全身炎症的指标相关。这方面的研究集中于了解脂肪组织淀粉样前体蛋白在肥胖和2型糖尿病中的调节，作为一种潜在的分子机制，将胰岛素抵抗状态与晚年阿尔茨海默病的发展联系起来。

DESCRIPTION (provided by applicant): Recent epidemiological studies show an association between mid-life obesity, type 2 diabetes mellitus (T2DM), and the development of Alzheimers Disease (AD). Altered processing of Amyloid Precursor Protein (APP) leads to increased neuronal production of pathologic amyloid-b (Ab) fragments, which is a major component of AD pathology. Dysregulated APP processing is associated with insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation, states which typify obesity and T2DM. Adipose tissue is a major site of altered metabolism in obesity and T2DM. It becomes chronically inflamed in obesity contributing in part to altered metabolic function of adipose tissue in T2DM. We recently reported APP is expressed in human adipose tissue cells, upregulated with obesity and T2DM, and correlated to insulin resistance and inflammatory markers. We also found elevated plasma Ab levels are correlated with adipocyte APP expression and measures of insulin resistance. In light of these data, we hypothesize that alteration of adipose tissue APP and Ab in obesity and T2DM is a putative mechanism linking insulin resistant states and AD. Our approach to this hypothesis focuses on whether changes in adipocytes and preadipocytes related to insulin resistant states alter the regulation and processing of adipose APP and will be tested in the following aims: Specific Aim 1: We will test whether adipose tissue cells produce significant amounts of Ab, if this production is a determinant of circulating Ab levels, and if this process is altered by obesity, insulin resistance, and T2DM. Specific Aim 2: We will test whether insulin, glucose, and / or pro-inflammatory factors directly regulate expression of APP or its processing enzymes in adipose tissue cells. Specific Aim 3: To determine whether Ab affects glucose uptake in adipose tissue cells through alterations of insulin receptor signaling and pro-inflammatory pathways. Each of these aims will generate independent and novel data contributing to understanding the role of adipose APP and Ab in insulin resistant states and may suggest new therapeutic targets or preventive strategies for therapy of AD and T2DM. Additionally this project constitutes a rigorous clinical research training program for the applicant with integrated basic and clinical studies and well matched didactics. PUBLIC HEALTH RELEVANCE: Recent epidemiological studies show an association between insulin resistant states such as obesity and type 2 diabetes mellitus and the development of Alzheimer's Disease, a sobering observation as obesity and diabetes are global epidemics. Cell biology studies strongly support the idea that insulin resistance induces cellular changes promoting Alzheimer's Disease; our clinical research group found Amyloid Precursor Protein, a major component of the pathology of Alzheimer's Disease, is expressed in adipose tissue, upregulated with obesity, and correlated with measures of insulin resistance and systemic inflammation. The studies in this application focus on understanding the regulation of adipose tissue Amyloid Precursor Protein in obesity and type 2 diabetes mellitus as a potential molecular mechanism linking insulin resistant states with developing Alzheimer's disease later in life.