Proteasome Augmentation Mitigates Age‐Related Cognitive Decline in Mice

The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related declines in proteasome activity is driven predominantly by reduced functionality of proteasome rather than altered composition. By overexpressing the proteasome subunit PSMB5 in the neurons of mice to increase the proteasome content and thus enhance its functionality, we slowed age-related declines in spatial learning and memory. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.