We propose to develop a therapy for neurodegenerative tauopathies that uses a recombinant adeno- associated viral (AAV) vector to achieve long-term, stable central nervous system (CNS) delivery of a therapeutic tau N-terminal antibody (TNT-Ab). To this end, we have developed an inducible AAV gene transfer system for regulated expression of TNT-Ab in the brain. The levels and duration of TNT-Ab expression can be controlled by oral administration of a small molecule drug. We hypothesize that TNT-Ab expressed in affected neural tissues will reduce tau-mediated pathology with concomitant improvement of Alzheimer's disease (AD). Since TNT-Ab is expressed locally in neural tissue, the blood brain barrier (BBB) will not prevent TNT-Ab from access to affected neurons. AAV-delivered TNT-Ab can solve the BBB problem of systemic protein therapy and represents a novel and potentially practical approach to the treatment of tauopathies such as AD. In phase I we will construct the vectors, and test their constitutive and inducible expression of TNT-Ab in vitro and in the brains of recipient mice. Phase II will focus on expanded proof-of-concept studies. Given the remarkable progress in using AAV therapeutically -- there are over 50 clinical trials using AAV as delivery vehicles, with several AD trials -- we are optimistic that our regulated AAV expression system for delivery of TNT-Ab to the brains of affected patients will provide a novel restorative therapy for devastating neurodegenerative tau-based diseases (tauopathies).