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 A 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, A can inhibit the proteasome, which aggravates the accumulation of abnormal proteins. Therefore, the goal of this project is to identify novel small molecules that can activate the proteasome to clear the abnormal protein aggregates and to restore normal neuron cell functions of AD-afflicted brain. This research will provide a strong foundation to the course of developing the proteasome activators as promising drug candidates for AD.