Aβ inhibits the proteasome and enhances amyloid and tau accumulation

The accumulation of misfolded protein aggregates is a common feature of numerous neurodegenerative disorders including Alzheimer disease (AD). Here, we examined the effects of different assembly states of amyloid beta (Aβ) on proteasome function. We find that Aβ oligomers, but not monomers, inhibit the proteasome in vitro. In young 3xTg-AD mice, we observed impaired proteasome activity that correlates with the detection of intraneuronal Aβ oligomers. Blocking proteasome function in pre-pathological 3xTg-AD mice with specific inhibitors causes a marked increase in Aβ and tau accumulation, highlighting the adverse consequences of impaired proteasome activity for AD. Lastly, we show that Aβ immunotherapy in the 3xTg-AD mice reduces Aβ oligomers and reverses the deficits in proteasome activity. Taken together, our results indicate that Aβ oligomers impair proteasome activity, contributing to the age-related pathological accumulation of Aβ and tau. These findings provide further evidence that the proteasome represents a viable target for therapeutic intervention in AD.