Identifying regulators of APP gamma secretase

描述（由申请人提供）：阿尔茨海默病（AD）是一种大脑神经退行性疾病，是最常见的老年痴呆症。导致AD的中心病理事件被认为是淀粉样斑块的积累，淀粉样斑块主要由一种被称为淀粉样β肽（a - β）的有毒肽在大脑中组成。a - β是通过两种蛋白酶的作用，通过蛋白水解加工而产生的，其中一种蛋白酶是分泌酶。γ分泌酶功能的异常作用是最常见的早发性家族性AD的基础。分泌酶存在于一个由四种基本成分组成的大的多蛋白复合体中：早老素、nicastrin、aph-1和pen-2。确定γ分泌酶活性受调节的机制将有助于加深对阿尔茨海默病发病机制的了解，并可能为开发新的诊断工具和治疗靶点提供见解。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder of the brain and the most common form of senile dementia. The central pathological event leading to AD is thought to be the accumulation of amyloid plaques consisting primarily of a toxic peptide known as amyloid beta peptide (A-beta) in the brain. A-beta is derived from APP by proteolytic processing via the action of two proteases, one of which is gamma secretase. The aberrant action of gamma secretase function underlies the most common early onset familial AD. Gamma secretase resides in a large multi-protein complex with four essential components: presenilin, nicastrin, aph-1 and pen-2. Identifying mechanisms by which gamma secretase activity is regulated should lead to an increased understanding of AD pathogenesis and may provide insight in developing new diagnostic tools and therapeutic targets. Drosophila has been used with great success as a molecular genetic tool to identify new genes and study essential biological processes. In Drosophila, the gamma secretase activity and its four essential components are functionally conserved. Thus regulators of gamma secretase identified in Drosophila are likely to be functionally conserved. We have developed a reporter system in the living Drosophila eye that allows us to visualize the endogenous level of gamma secretase activity. Using these flies as a genetic background, we have carried out genetic screens and have identified several candidates to be characterized further. The specific aims of this proposal are: 1. Carry out loss-of-function screens, clone candidate genes and characterize their sites of function. 2. Characterize gain-of-function modifiers of gamma-secretase activity. 3. Determine how the candidate gene interacts with genes encoding components of gamma-secretase complex, aph-1, pen-2, nicastrin and presenilin