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。AD的一个重要风险因素是中年肥胖。肥胖本身也代表了美国的一个巨大的健康问题，其建议的流行水平。因此，任何改善其中一种或两种病症的策略在治疗上都是非常有吸引力的。我们认为AD和肥胖之间的关系是不相关的，但可能有一个共同的病理生理。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形式AD的原因。然而，我们的初步数据表明，APP是至关重要的体重增加和相关的大脑和脂肪的变化，发生在高脂肪饮食诱导的肥胖症的小鼠模型。APP表达实际上是脂肪酸有效摄取到细胞中所必需的。因此，我们假设APP调节不同的细胞分化，特别是涉及脂质代谢的变化，调节脂肪细胞，神经元和巨噬细胞/小胶质细胞在饮食诱导的肥胖症。突变APP的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设，量化野生型和突变型APP的能力和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表型在体外。然后，我们将确定APP在饮食诱导的肥胖症中组织特异性变化中的作用， 使用表达野生型和突变型APP的小鼠与APP-/-小鼠进行体内比较。通过定义APP的正常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如何直接导致饮食诱导的肥胖，并可能导致AD的进展。这不仅提供了这两种疾病的共同机制病理生理学，而且还靶向APP及其相关的信号传导反应用于治疗干预。

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.