At the cellular level Alzheimer’s disease (AD) is characterized by the accumulation of misfolded and damaged proteins. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are Amyloid β (Aβ), Tau, and sometimes α-synuclein (α-syn). A vast body of literature supports the notion that the cell’s protein degradation systems do not function sufficiently enough in AD to clear these misfolded proteins. The cell’s primary system for the degradation of such misfolded or damaged proteins is the Ubiquitin Proteasome System (UPS). We have recently found that pathologically relevant oligomeric forms of Aβ, Tau, and α-syn can potently and directly inhibit isolated 20S and 26S proteasomes, even inhibiting ubiquitin- dependent protein degradation in vitro. Based on our preliminary data we hypothesize that such pathological oligomers contribute to AD pathogenesis by directly inhibiting proteasome function in neurons. What we do not know is if proteasome inhibition by such oligomers can cause AD related neuronal dysfunction, nor do we know the molecular mechanisms involved. We propose to fill this gap in knowledge by 1) elucidating the precise mechanism of proteasome inhibition by these oligomers in vitro and in vivo 2) generating proteasomes that are hyper-active or resistant to inhibitory oligomers and 3) testing if hyper-active or oligomer resistant proteasomes can rescue neuronal function in cellular and animal models of AD. Our proposal is innovative because we have generated highly novel animal model and preliminary data that supports a novel mechanistic hypotheses, which addresses a fundamental component of AD. Extending these studies will allow us to generate disease resistant proteasomes allowing us to conclusively determine if direct proteasome impairment by AD related oligomers can cause neuronal dysfunction. This contribution is significant because it will fill a gap in our knowledge by demonstrating that the pathological oligomers associated with AD cause neuronal dysfunction, at least in part, by directly inhibiting the proteasome. In addition, this study will also demonstrate if proteasome activation can protect neurons from AD related proteotoxicities. These outcomes are expected to have a positive impact because they demonstrate that the proteasome is a prime therapeutic target to treat Alzheimer’s disease and provides a precise molecular mechanism that can be exploited for pharmacological development.