(300 WORDS MAX)Human tauopathies are a diverse class of devastating neurodegenerative diseases notably Alzheimer disease (AD), where there is not any effective therapy currently. The common hallmark change in the brain of these diseases is neurofibrillary tangles made of tau that is phosphorylated on specific amino acid motifs (pSer/Thr-Pro-tau). We have previously found that the pThr231-Pro motif in tau exists in the two distinct conformations and identified the unique prolyl isomerase Pin1 to accelerate their conversion. Importantly, Pin1 is inhibited in human AD brains, whereas preventing Pin1 inhibition is associated with delayed onset of human AD. Moreover, loss of Pin1 in mice causes tangle formation and neurodegeneration, whereas neuronal Pin1 overexpression prevents tangle formation in mice. Human Pin1 gene is located at 19p13.2, a new late onset AD locus. Thus, Pin1 helps keep AD at bay presumably via modifying tau structure. This idea has been supported independently by the recent findings that Thr231 phosphorylation is the earliest detectable tau phosphorylation event during early stages of AD. We have now developed novel technologies to generate antibodies to visualize how Pin1 modifies tau structures and identified abnormal pT231-tau structure that appears early in mild cognitive impairment brains and further accumulates as AD progresses. Moreover, Pin1 deletion or overexpression reduces or increases this pathological pT231-tau structure, respectively, which may explain the ability of Pin1 to protect against AD. This proposal will use the novel technologies that we have just created to develop active and passive immunization that specifically targets the pathological pT231-tau structure in tauopathies and establish proof of concept for such novel therapeutic approach for treating AD. Given that this immunotherapy specifically targets only an important disease-causing early event in the development of AD, we believe that this approach would be highly specific and effective for treating AD and other tauopathies.