(300 WORDS MAX) Aberrant accumulation of tau protein underlies tangle formation as well as neuronal death in Alzheimer's disease (AD). Thus, agents that can effectively and safely ameliorate tauopathy represent promising therapeutic and potential prophylactic treatments in AD. The major goal of this proposal is to develop and validate screening assays for small molecule inhibitors of pathogenic tau accumulation in embryonic stem (ES) cell-derived primary neurons from mouse models of tau pathology. Specifically, ES cells isolated from a mouse model with AD type tauopathy (hTau mice), will be subjected to a highly reproducible differentiation protocol to which produces a highly reproducible a pyramidal neuron culture. Phenotypic cell-based assays will be established to monitor early and disease-relevant alterations in tau metabolism (e.g. the protein level and phosphorylation status of human tau). Given the relevance of proposed tauopathy mouse models to AD and the physiological nature of the proposed neuronal assays, successful completion of our studies will establish a drug discovery platform which has a highly augmented probability of success for the identification of physiologically relevant therapeutic candidates. While human patient derived stem cells carry great promise, their productive and reliable use in drug discovery remains challenging due to difficulties in consistent maintenance, passaging and differentiation into functional neurons. Thus, our system, based on a mouse ES cell-derived neuronal model, is likely to convey an immediate impact in the field by enabling drug discovery efforts in disease-relevant primary neurons. The proposed research will be conducted in close collaboration with the proposal by Dr. Wai-Haung Yu (Columbia University): we will test and validate bioactivities of compounds identified in Dr. Yu's proposed screens for small molecule modulators of autophagy and tau degradation.