APP Regulates Brain and Adipose Changes in Obesity

描述（由申请人提供）：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。就其本身而言，肥胖也代表了美国巨大的健康问题，因为它的流行程度。因此，任何改善一种或两种情况的策略在治疗上都极具吸引力。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，编码淀粉样蛋白前体蛋白APP的基因突变是导致常染色体显性AD的原因。然而，我们的初步数据表明，APP对于体重增加以及在高脂肪饮食诱导的肥胖小鼠模型中发生的相关大脑和脂肪变化至关重要。APP表达实际上是细胞有效摄取脂肪酸所必需的。因此，我们假设APP调节多种细胞分化，特别是在饮食诱导肥胖过程中调节脂肪细胞、神经元和巨噬细胞/小胶质细胞的脂质代谢的变化。突变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。我们将首先验证这一假设，量化野生型和突变型APP的能力以及任何相关的信号或处理，以调节脂肪细胞、巨噬细胞/小胶质细胞和神经元的体外表型。然后，我们将确定APP在饮食引起的肥胖期间组织特异性变化中的作用

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.