ABSTRACT Virtually all neurodegenerative diseases are characterized by the accumulation of proteins that are thought to play a significant role in disease pathogenesis. One of the cell’s primary systems for the removal and degradation of misfolded or damaged proteins is the Ubiquitin Proteasome System (UPS). However, numerous studies have shown significant impairment of the UPS in essentially all of these neurodegenerative diseases. What is not known is why protein degradation is impaired, allowing misfolded proteins to accumulate and become toxic in these diseases, or if the stimulation of the proteasome function could be a viable treatment. All of these diseases are characterized by their own unique protein deposits. However, the microtubule associated protein tau is unique in that it is ubiquitously implicated in most neurodegenerative diseases as the secondary protein involved in these protein deposits. The preliminary data that we have gathered led us to the central hypothesis that tau oligomers bind to the 20S proteasome, and inhibit protein degradation by stabilizing the closed gate conformation. The first aim in this proposal is to determine the molecular mechanism by which soluble tau oligomers impair the proteasome. This will allow us to identify and understand at a molecular level, a general mechanism of toxicity that could be common to many neurodegenerative diseases. The second aim in this proposal is to determine the feasibility of increasing proteasome activity to reduce toxicity due to the presence of specific oligomers in neuronal cell models. The proposal is expected to have an important and positive impact because it will allow us to identify and understand, at a molecular level, a general mechanism of toxicity in Alzheimer’s disease that could be common to many neurodegenerative diseases; and furthermore, it will assess the feasibility of reversing this toxicity to potentially treat neurodegenerative diseases.