Application of Activity‐Based Probe, MV151, in the Mammalian Nervous System Reveals New Insights into Proteasome Changes in Human Alzheimer's Disease Brain

Abstract

Proteasome complexes play a critical role in human brain health and disease. Despite enormous effort, proteasome composition, activity, and abundance in the human brain remains poorly understood. In this study, we describe a series of tools that can measure the catalytic activity and levels of individual proteasome β‐subunits and distinct proteasome complexes in mammalian tissue. Adapting these tools to brain tissue from human Alzheimer’s disease (AD) patients, we found that the human brain has a high abundance of catalytically active 20S proteasomes and that these 20S proteasomes exhibit higher total activity in AD when compared to unaffected controls. Additionally, we showed that 20S proteasome abundance is inversely correlated with the severity of the AD case. Taken together, our results indicate that while 20S proteasome abundance is decreasing in AD patient brains, this is counter‐balanced by an increase in proteasome activity. We now propose that homeostasis of 20S proteasome activity is a hallmark of human brain health, and changes in abundance and activity are correlated to the severity of AD disease. This discovery sets the stage for further investigation into 20S proteasome activity in neurodegenerative disease states.