APP Regulates Brain and Adipose Changes in Obesity

描述(申请人提供)：阿尔茨海默病(AD)估计影响超过500万美国人。阿尔茨海默病的一个重要风险因素是中年肥胖。肥胖本身也代表着美国人对健康的巨大担忧，因为美国人建议的流行病水平。因此，任何改善其中一种或两种情况的策略在治疗上都是非常有吸引力的。我们认为AD与肥胖之间的关系并不相关，但可能存在共同的病理生理机制。众所周知，编码淀粉样前体蛋白APP的基因突变是常染色体显性阿尔茨海默病的原因。然而，我们的初步数据表明，在高脂饮食诱导的肥胖小鼠模型中，APP对于体重增加以及相关的大脑和脂肪变化是至关重要的。APP的表达实际上是细胞有效吸收脂肪酸所必需的。因此，我们假设APP调节不同的细胞分化，特别是在饮食诱导的肥胖过程中，调节脂肪细胞、神经元和巨噬细胞/小胶质细胞的脂代谢的变化。突变的APP对这种生物学的失调或改变将在肥胖期间产生影响，但更重要的是，在AD期间。我们将首先测试这一假说，量化野生型和突变型APP以及任何相关的信号或处理在体外调节脂肪细胞、巨噬细胞/小胶质细胞和神经元表型的能力。然后，我们将确定APP在饮食诱导的肥胖过程中组织特异性变化中的作用 体内使用野生型和突变型APP表达的小鼠与APP-/-小鼠进行比较。通过确定APP的正常形式和突变形式在调节脂肪组织库和大脑中的细胞表型中的作用，我们将解释APP如何直接促进饮食诱导的肥胖，并可能促进AD的进展。这不仅为这两种疾病提供了共同的机制病理生理学，而且针对APP及其相关的信号反应进行治疗干预。 与公共健康相关：这项研究将验证淀粉样前体蛋白调节细胞代谢和利用脂肪酸能力的新机制。在饮食诱导肥胖的情况下，这种Biolog对于脂肪组织以及大脑和免疫细胞的变化尤其重要。由于突变形式的淀粉样前体蛋白表达可导致阿尔茨海默病，我们推测淀粉样前体蛋白在调节脂质代谢中的作用也与阿尔茨海默病的发病机制有关。明确淀粉样前体蛋白在饮食诱导的肥胖中的功能不仅将有助于深入了解肥胖的病理生理学，还将有助于了解阿尔茨海默病的病理生理学。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is estimated to affect over 5 million Americans. A significant risk factor for AD is particularly mid-life obesity. In itself, obsity also represents a tremendous health concern for the U.S. with its suggested epidemic levels. Therefore, any strategy to ameliorate either or both conditions is extremely attractive therapeutically. We propose that the relationship between AD and obesity is not correlative but that there may be a common pathophysiology. It is well known that mutations in the gene coding for amyloid precursor protein, APP, are responsible for autosomal dominant forms of AD. However, our preliminary data indicates that APP is critically required for weight gain and the associated brain and adipose changes that occur in a murine model of high fat diet-induced obesity. APP expression is actually required for efficient uptake of fatty acids into cells. Therefore, we hypothesize that APP regulates diverse cellular differentiation involving, in particular, changes in lipid metabolism that regulates adipocytes, neurons, and macrophage/microglia during diet-induced obesity. Dysregulation or alteration of this biology by mutant APP will have ramifications during obesity but, more importantly, during AD. We will first test this hypothesis quantifying the ability of wild type and mutant APP and any associated signaling or processing to regulate adipocyte, macrophage/microglia, and neuron phenotype in vitro. We will then define a role for APP in tissue specific changes during diet-induced obesity in vivo using wild type and mutant APP expressing mice compared to APP-/- mice. By defining the role of normal and mutant forms of APP in regulating cellular phenotype in adipose tissue depots and brain we will explain how APP contributes directly to diet-induced obesity and possibly to progression of AD. This not only offers a common mechanistic pathophysiology of these two diseases but also targets APP and its associated signaling response for therapeutic intervention. PUBLIC HEALTH RELEVANCE: This study will validate a novel mechanism by which amyloid precursor protein regulates the ability of cells to metabolize and utilize fatty acids. This biolog is particularly important for the changes that occur in adipose tissue but also in the brain and immune cells during the condition of diet-induced obesity. Because expression of mutant forms of amyloid precursor protein produces Alzheimer's disease, we speculate that the role of amyloid precursor protein in regulating lipid metabolism is also related to mechanisms of Alzheimer's disease. Defining the function of amyloid precursor protein in diet-induced obesity will not only offer insight into the pathophysiology of obesity but also that of Alzheimer's diseas.