The role of Drosophila APPL (Amyloid Precursor Protein Like) Protein in brain function and behaviour

淀粉样前体蛋白（APP）已被确定在寻找阿尔茨海默氏病的病原体。脑中APP蛋白水解过程的改变，导致神经毒性Aβ-淀粉样肽的产生增加和随后的斑块形成是阿尔茨海默病的标志。APP基因从线虫到人类都是保守的，但其内源性功能仍然很难理解。APP基因的进化保守性表明其对脑的完整性和功能具有有益的内源性作用。不幸的是，对果蝇和小鼠中这些基因的无效突变的分析没有提供任何信息，因为检测到的缺陷是微妙的。该建议的中心假设是，果蝇APP直系同源蛋白APPL的平衡差异处理对中枢神经系统的功能具有至关重要的作用。全长APPL和其蛋白水解片段的改变的比率将不同地影响脑连接和突触效率。神经元网络的突触功能和连通性的变化最敏感地通过行为的变化来监测。我们建议进行一个详细的分析的行为变化引起的遗传改变水平的APPL和其片段在老龄化苍蝇。通过这种方法，我们将确定单个APPL片段对大脑完整性和功能的有益或有害作用。

The amyloid precursor protein (APP) has been identified in the search for the causative agent of Alzheimer’s disease. Altered proteolytic processing of APP in the brain, leading to increased production of the neurotoxic Aβ-amyloid peptide and subsequent plaque formation is a hallmark of Alzheimer’s disease. The APP gene is conserved from nematodes to man but its endogenous function remains elusive by large. The evolutionary conservation of APP genes suggests a beneficial endogenous role for the brain integrity and function. Unfortunately the analyses of null mutations for these genes in flies and mice have been uninformative because the detected defects are subtle. The central hypothesis of this proposal is that the balanced differential processing of the Drosophila APP ortholog protein APPL has a crucial role for the function of the central nervous system. Altered ratios of full length APPL and its proteolytic fragments will differentially affect brain connectivity and synaptic efficiency. Changes in synaptic function and connectivity of neuronal networks are most sensitively monitored by changes in behaviour. We propose to conduct a detailed analysis of the behavioural changes induced by genetically altered levels of APPL and its fragments in aging flies. By this means we will identify the beneficial or detrimental role of individual APPL fragments for brain integrity and function.