Dissecting the Toxicity of Glial and Neuronal Expression of APP in the Brain

 描述(申请人提供)：在过去的几年里，人们致力于研究淀粉样前体蛋白(APP)在阿尔茨海默病(AD)中的作用。关键目标之一是了解APP在AD中的确切作用。APP显然参与了AD的发病机制。例如，第一个被确认为常染色体显性阿尔茨海默病的原因的基因突变是在APP基因中。同样，APP基因的重复也是发展为AD的风险因素。APP在神经元和神经胶质细胞中都有表达，虽然人们已经做了很多工作来了解APP在神经元中的作用或处理，但还没有研究APP在神经胶质细胞中表达和处理的重要性或相关性。因此，我们对APP在胶质细胞中在AD发生发展中的作用知之甚少。我们在果蝇的大脑中开发了一个稳健的APP-GOF模型。我们可以在神经胶质细胞或神经元中特异性地表达这一点。当我们在胶质细胞中表达APP并与神经元表达相比较时，我们发现APP的沉积模式、APP的加工以及由这种表达诱导的杀伤力都有所不同。我们进一步发现，致死性与除Abeta以外的特定加工肽严格相关；其水平随着人BACE的共同表达而增加，并导致与单独表达APP相比更大的致死性。这些主要结果导致我们制定实验，剖析APP在神经胶质细胞中表达时的作用、处理和毒性，并将其与神经元中的APP进行比较。因此，我们的具体目标是：1)分析APP在胶质细胞中的表达及其致死效应；2)分析APP加工肽在胶质细胞和脑内神经元中表达的影响；3)对APP-GOF的隐性修饰物进行条件遗传筛选。我们相信，这些目标一旦完成，将有助于我们理解APP在神经胶质细胞中所起的作用，以及它在神经病理学和疾病发展中的作用。这些研究还可能在APP介导的途径中发现新的参与者(S)。

 DESCRIPTION (provided by applicant): Over the last several years, much effort has been devoted to studying the role of Amyloid Precursor Protein (APP) in Alzheimer's disease (AD). One of the key goals has been to understand the precise role of APP in AD. APP is clearly involved in the pathogenesis of AD. For instance, the first gene mutation identified as a cause for autosomal dominant form of AD is in the APP gene. Similarly, duplication for the APP gene is a risk factor for developing AD. APP is expressed both in neurons and glia, and while much work has been directed towards understanding its role or processing in neurons, the importance or the relevance of expression and the processing of APP in glia has not been examined. Thus, we know very little about the role of APP in glia in the development of AD. We have developed a robust APP-gain of function (APP-GOF) model in the Drosophila brain. We can express this specifically in glial cells or neurons. When we expressed APP in glia and compared to neuronal expression, we found differences in both the pattern of deposition of APP, processing of APP, and lethality induced by such expressions. We further found that the lethality strictly correlated with a specific processed peptide other than Abeta; the level of which increased with the co-expression of human BACE and resulted in a greater lethality compared to APP expression alone. These main results led us to formulate experiments to dissect the role of APP, its processing and toxicity when expressed in glial cells, and compare this with APP in neurons. Thus, our specific aims are: 1) Analyze the processing and the lethal effects of expression of APP in glial cells, 2) Analyze the effects of expression of processed peptides of APP in glia and neurons in the brain, and 3) Perform a conditional genetic screen for recessive modifiers of APP-GOF. We believe that these aims when completed, will contribute significantly to our understanding of the role played by APP in glia and its contribution to the development of the neuropathology and the disease. These studies will also likely identify new players in the APP-mediated pathway(s).