The proteasome serves as a major protein quality control system inside the cell. Dysfunction of this system has been associated with Alzheimer's disease (AD) pathogenesis. Amyloid β accumulation is considered as the central molecular event in the development of AD. This accumulation can result from dysregulated proteolysis of its precursor, APP. Here, we will review the evidence that links proteasome dysfunction to altered APP metabolism, and summarize recent progress in identifying the regulators of APP ubiquitination. Pinpointing UPS components that are APP-specific could lead new pharmaceutical strategies to combat AD.