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

淀粉样前体蛋白(APP)已经在寻找阿尔茨海默病的病原体的过程中被确定。APP在大脑中的蛋白分解过程改变，导致神经毒性A-β-淀粉样多肽的产生增加，随后形成斑块是阿尔茨海默病的一个特征。APP基因从线虫到人类都是保守的，但它的内源功能基本上仍然难以捉摸。APP基因的进化保守表明，对大脑的完整性和功能具有有益的内源性作用。不幸的是，在果蝇和老鼠身上对这些基因的零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。这一建议的中心假设是，果蝇APP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。改变全长APPL及其蛋白分解片段的比例将不同地影响脑连接和突触效率。神经网络的突触功能和连通性的变化最敏感地受到行为变化的监测。我们建议对APPL及其片段的遗传改变在衰老果蝇中引起的行为变化进行详细分析。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利或有害作用。

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.