A novel systems analysis of a synaptic gene network

近几十年来，随着老年人口的增加，阿尔茨海默病（Alzheimer's disease， AD）的发病率越来越高

With the increase of the elderly population in recent decades, Alzheimer's disease (AD) is quickly becoming a public health concern. The disease causes loss of memory, confusion and affects decision-making. With the few exceptions of familial AD cases linked to APP and ApoE4 as a risk factor, most AD cases have unknown ethiology. Therefore, a major effort has been directed to identify genes associated with AD with the goal of developing better diagnostic tools and new therapies for the disease. The majority of the strategies to identify AD markers, targets, predictors and risk factors still rely on Genome Wide Association Studies (GWAS), which are known for high costs and a high rate of false positives. In contrast, our study starts with a synaptic network of proteins required for decision-making in Drosophila, which is conserved in flies and in humans. This synaptic network is composed of genes that have DNA binding sites of DATI, a conserved transcription factor that allows female flies to either accept or reject males. Remarkably, 88% of the genes in this network are present in the human genome and 100% of these human genes also contain DATI binding sites, indicating that this is a very deeply conserved gene network likely to be of significance to understand higher cognitive functions. Consistent with this view, 10% of the proteins of the network interact with APP and 13% of the genes listed in AGORA as candidates for AD are part of this network. Together, these data make a strong case that this network is significant for understanding AD. In addition to identifying these genes, this project seeks to understand how these genes lead to the emergence of cognitive functions. To begin addressing this question, we have been using a series of tools to analyze multidimensional data in 3D space in intact brains. These tools allow us to analyze in fluorescently labeled neurons how the knockdown of a gene of the network modifies the levels and localization of other genes of the network using Geographic Information Systems. This administrative supplement request will partially support the acquisition of a new instrument, the Zeiss LSM900 confocal microscope with Airyscan 2. To a significant extent, the throughput of these analyses depends on the scanning speed of the confocal microscope, the resolution required, the sensitivity and automation in the process. We expect that the acquisition of this new compact confocal system will allow us to increase the throughput and resolution of our analyses, ultimately increasing the impact of our study.