Description: Several neurological disorders, including Alzheimer's disease and frontotemporal dementia with parkinsonism (FTDP) are characterized in part by neurofibrillary tangles made up primarily of the protein tau. While useful mammalian models of tauopathy have been developed, a need exists for a vertebrate model of tauopathy that is amenable to high throughput drug screening and rapid target validation. We propose to create transgenic zebrafish that express human tau specifically in neurons. In Phase I, the consequences of transient overexpression of tau will be analyzed by immnohistochemistry, western blot analysis, and visualization of fluorescent neurons in living embryos. Stable transgenic lines will also be generated. In Phase II, the assay will be further validated and automated in preparation for screening compound libraries. The eventual goal is to identify compounds that can protect neurons from tau-induced toxicity. In addition, zebrafish genes that affect tau aggregate formation can be rapidly identified, potentially opening up new avenues for Alzheimer's disease and FTDP drug discovery. The assay will be marketed to pharmaceutical companies to aid their drug discovery efforts. In addition, neuroprotective compounds identified using the assay will be developed as therapeutics for neurological disorders. Relevance: The purpose of this proposal is to accelerate drug discovery for devastating neurological diseases, such as Alzheimer's disease. We propose to do this by developing a new animal model of neurological disease that can be used to screen a larger number of compounds than is currently possible. ? ? ?
