(300 WORDS MAX.) 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 Aβ 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. The majority of effort on Hsp90 inhibitors has been for cancer applications. This proposal is to optimize existing Hsp90 inhibitors for brain penetration in order to develop their potential for AD. These inhibitors can be tested in future studies for efficacy in animal models of AD and then further developed in preclinical studies with the goal of advancing unique molecules as a new generation of drugs to treat AD.