There is currently no effective treatment for Alzheimer's disease. Most of the focus of current drug development has been on the amyloid-beta peptide that aggregates in amyloid plaques and is one of the two major hallmarks of the disease. The aim of this proposal is to develop further therapy that targets neurofibrillary tangles that are the other major hallmark of the disease, and correlate better with the degree of dementia than amyloid plaque deposition. Furthermore, we propose to develop an in vivo imaging technique that will clarify the neurotoxic effects of tau aggregates that form the tangles, and this approach may potentially be used to diagnose the disease in the future. Presently, Alzheimer's disease can only be diagnosed by analyzing brain sections following autopsy. We recently published the first article that demonstrates that immunotherapy targeting pathological tau protein clears these aggregates in a mouse model with accompanying behavioral improvements (Asuni et al., Journal of Neuroscience, 27(34):9115-29, 2007). In addition, our preliminary data shows substantial cognitive improvements and clearance of tau aggregates with this type of therapy in another mouse model. Our proposed studies should clarify which type of tau immunotherapy is likely to be safe and effective, and should identify a vaccine for clinical trials. Our imaging approach is also supported by promising preliminary data that shows that we can detect the neurotoxic effect of tau aggregates, both at early and late stages of the pathology. This type of brain imaging in live animals should clarify the effects of tau aggregates on neuronal function and may allow a rapid in vivo evaluation of therapeutic approaches targeting pathological tau aggregates, which may substantially shorten these types of studies. This diagnostic approach may potentially be used in humans in the future.Specific Aim 1 is to improve the therapeutic effect of active immunization against pathological tau, clarify its mechanism and to determine if this approach can reverse tau pathology. Specific Aim 2 is to determine how tau aggregates and their clearance influence neuronal activity in vivo, and to monitor treatment efficacy with manganese-enhanced magnetic resonance brain imaging.