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

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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.