The aims of the program as a whole are to explore the functional and pathological consequences of pathogenic tau formation in a mouse model of neurodegeneration with special reievance to Alzheimer's disease. Project 5 aims to examine three potentially pathogenic pathways that may be involved in the initiation and progression of involved tauopathy; the role of kinases in pathogenesis and the impact of kinase inhibitors, 2) the role of tau aggregation and the impact of aggregation inhibitors, and 3) the role of elevated Abeta and the effect of Abeta reduction on plaque and tangle formation. Each of these aims is integrally linked to the aims of other projects on the PPG, and the overall aim of the PPG to examine the neurobiology of tauopathy. In addition, information will be generated as to the feasibility of targeting these pathways therapeutically. To address these aims, we have developed a new mouse model of tauopathy, by expressing all six isoforms of wild-type human tau with the correct temporal and spatial distribution in mice in the absence of mouse tau. These mice show pathological changes that are very relevant to tauopathy, and AD especially, including a compartmental switch from an axonal distribution of normal soluble tau, to accumulation of hyperphosphorylated, insoluble tau in the somatodendritic compartment of neurons. This is accompanied by an age-related, progressive increase in tau hyperphosphorylation, conformational alterations of tau, the formation of filamentous tau aggregates and neurodegeneration and cell death of neocortical and hippocarrrpal neurons. These mice are ideal subjects in which to examine mechanisms underlying pathogenesis, and validate them using potentially beneficial therapeutic approaches.