Both frontotemporal dementia (FTD) and Alzheimer¡¯s disease (AD) are characterized by aggregation and aberrant accumulation of microtubule-associated protein tau in nerve cells in the brain. A small percentage of FTD are also shown to be caused by genetic mutations in the gene encoding tau (MAPT), further supporting the role for tau in the pathogenesis of FTD. Therefore, therapeutic agents that can effectively and safely ameliorate tauopathy represent promising therapeutic and potential prophylactic treatments in neurodegenerative conditions associated with neurodegenerative disease with profound tau pathology, such as FTD and AD. The major goal of this proposal is to develop and validate screening assays and perform high throughput screening for small molecule modulators of tau metabolism in embryonic stem (ES) cell-derived primary neurons from mouse models of tau pathology. Specifically, we will attempt to identify compounds that can stimulate tau turnover and/or decrease the stability via different mechanisms, thereby alleviating the tau aggregation and tau-associated nerve cell damage. Successful completion of our studies will establish a new drug discovery platform to identify promising therapeutic candidate molecules for the treatment of AD and FTD.