Alzheimer's disease (AD) affects more than 5 million Americans and is a progressive neurodegenerative disorder that causes cognitive dysfunction, memory loss, and eventual death. Currently, no drugs have been shown to halt disease progression. Efforts to develop effective AD treatments have focused on approaches to attenuate the functions of Ab either by preventing its expression or facilitating its removal from the brain. A promising target has recently been identified, the chaperone protein heat shock protein 90 (Hsp90). Hsp90 has important roles in promoting disaggregation of misfolded proteins and protein degradation. In addition, recent evidence indicates a role of Hsp90 in maintaining functional stability of neuronal proteins even when they are abnormal, therefore allowing the accumulation of toxic aggregates. We developed a novel small molecule Hsp90 inhibitor that is orally active and penetrates the brain. We showed in mouse model of human tauopathy that the aberrant tau proteins ('tangles') were significantly reduced in the brain and cerebrospinal fluid of mice treated for 28 days with this drug candidate. This proposal is to conduct studies to understand the safety margin of this drug candidate and other studies to meet regulatory requirements. We will also initiate clinical phase 1a study in human. To our knowledge, this will be the first Hsp90 inhibitor drug candidate to enter clinical trials for the treatment of AD and offer a new approach to treat AD by targeting tangles.