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 (A beta) on proteasome function. We find that A beta 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 A beta oligomers. Blocking proteasome function in pre-pathological 3xTg-AD mice with specific inhibitors causes a marked increase in A beta and tau accumulation, highlighting the adverse consequences of impaired proteasome activity for AD. Lastly, we show that A beta immunotherapy in the 3xTg-AD mice reduces A beta oligomers and reverses the deficits in proteasome activity. Taken together, our results indicate that A beta oligomers impair proteasome activity, contributing to the age-related pathological accumulation of A beta and tau. These findings provide further evidence that the proteasome represents a viable target for therapeutic intervention in AD. Published by Elsevier Inc.