(300 WORDS MAX) Alzheimer's disease (AD) is a terminal brain disease that ranks 7th in the leading causes of death in America. AD causes the loss of memory, thinking skills, and eventually the ability to perform simple tasks. The AD related social and economic impacts are enormous. There are 5.3 million AD patients currently living in the United States with the majority at age 65 or older. As the population continues to age, the number of AD cases will greatly increase. Although tremendous effort has been made in research, there are no known drugs that can cure the disease. There has been an increase in evidence suggesting that buildup of abnormal protein aggregates, such as p-tau and AƒÒ in brain cell, are the major factors that cause the AD. Thus, we hypothesize that increase of protein degradation to remove the aberrant protein aggregates could be an attractive strategy for the treatment of AD. The proteasomes are cellular machineries responsible for intracellular degradation of damaged, unwanted, and mis-folded proteins. However, AƒÒ can inhibit the proteasome, which aggravates the accumulation of abnormal proteins. Therefore, the goal of this project is to synthesize novel small molecules that can activate the proteasome to clear the abnormal protein aggregates. The rationale is that proteasome activators will enhance the proteasome activity, as a result, clear aberrant protein aggregates, and restore normal neuron cell functions of AD-afflicted brain. To achieve this goal, we have been synthesizing novel proteasome activators using lithocholic acid as a scaffold. Our preliminary results are encouraging in that the synthesized novel lithocholic acid derivatives can activate the proteasome and antagonize the adverse effect of AƒÒ on proteasome inhibition. Thus, it is expected that completion of this study will provide a strong foundation to the course of developing the proteasome activators as promising drug candidates for AD.