Validation and Characterization of Tau Modifiers In Vivo

Project Summary

Neurofibrillary tangles containing tau are a hallmark of Alzheimer's disease. However, little is known about ways to protect brain cells from degeneration caused by tau. We looked at gene expression in several parts of the brain of mice expressing human tau including a mutation that causes FTD. This was done in combination with testing in the simple fruit fly. We identified several novel modifiers of tau neurotoxicity including the highly conserved protein, puromycin-sensitive aminopeptidase (PSA). Here, we propose further studies of the role of PSA in tauopathy, and plan to validate other genes identified as putative protective or susceptibility genes in the transgenic human tau P301L mouse model. These will involve crossing fruit flies that express tau with other lines that have greater and/or lesser expression of the genes identified in the mouse. Genes that succeed in changing tau toxicity can easily be identified under the microscope by examining the size of the fly eye. Validation and characterization of mechanisms of action of tau modifiers using the fly model will provide a first step toward identifying those modifiers which are most promising as therapeutic targets for AD; these may then be further studied in cell culture and mice.