Comparative Analysis of Transcriptome Profiles of Neural Stem/Progenitor Cells in Mouse and Zebrafish Brains after Amyloid-beta-42 Deposition

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In this proposal, we are aiming to compare the molecular response of neural stem/progenitor cells (NSPCs) of zebrafish and mouse after toxic aggregation amyloid-beta42, which is a major hallmark of Alzheimer's disease. We aim to find out the molecular differences between the NSPCs of zebrafish and mouse to hypothesize on a molecular framework of regenerative ability after neurodegeneration. We have recently found that in adult zebrafish brain, Amyloid-beta42 causes cell death, synaptic degeneration, inflammation and memory loss as in our brains. Interestingly, zebrafish also increased the proliferation of NSPCs, and produces more neurons even though Amyloid-beta42 toxicity. In our brains, we cannot activate our NSPCs to proliferate more, and produce more neurons, which is one of the major reasons why we cannot cope with neurodegenerative diseases by mounting a regeneration response, or activate a "plasticity cascade". Since our mammalian brains cannot fulfill such an increase in "plasticity", we hypothesized that we could learn from zebrafish how to coax our NSPCS to perform better in case of Alzheimer's disease. We are planning to do this by analyzing the gene expression in stem cells of zebrafish and mouse using already established Alzheimer disease models (our model in zebrafish, and a widely-used model in mouse). By performing protocols of deep sequencing of the gene expression and subsequent bioinformatics analyses, which are optimized in our laboratory, we anticipate to find out the genes that may make the difference between the "plasticity" capacities of zebrafish NSPCs and mammalian NSPCs. By pinpointing which genes must be activated or deactivated in disease conditions in order to fulfill a successful proliferation response of our brain stem cells, we will investigate the causes and consequences of Alzheimer's disease in the stem cells of our brain bettwe, and will also be able to design novel regenerative therapies based on our fundamental research.