PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) affects 5.5 million Americans, producing cognitive deficits and mortality. There are very limited treatment options for AD, making development of interventions to slow or reverse AD symptoms a critical area of research. Proteasome function declines in the brain with age, an impairment that is even more pronounced in patients with AD; this is also seen in animal models of AD. Using in vivo invertebrate and in vitro vertebrate models of AD, we have found that genetic and pharmacologic augmentation of the proteasome can delay AD-like cognitive and neurodegenerative symptoms, while reducing proteasome function accelerates AD progression. Building on these findings, we now propose to investigate (a) the mechanism of action and (b) efficacy of proteasome manipulation as a possible intervention for AD. This proposal has three goals: 1) To determine if drug and genetic manipulation of proteasome function reduce AD-like symptoms in mice that model the disease. This is a natural progression from our prior studies of these interventions in flies and cell culture and is supported by our strong preliminary data in mice. 2) To elucidate how proteasome dysfunction is linked to AD progression. We present, and test, two hypotheses to explain this interplay. The first hypothesis is that the proteasome has a key role in prevention of AD progression through degradation of the β-amyloid (Aβ) machinery, specifically, amyloid precursor protein (APP), β-secretase (BACE1), and γ-secretase activating protein (GSAP), all of which are targets of proteasome degradation. If so, it would indicate that age- related declines in proteasome function result in accumulation of these proteins, which drives AD pathogenesis. The second hypothesis is that proteasome dysfunction, triggered by Aβ inhibition, drives downstream neurodegeneration rather than altering Aβ accumulation. Proteasome dysfunction on its own causes neurodegeneration and synaptic loss. If our findings are consistent with this hypothesis, it would indicate that proteasome dysfunction caused by Aβ inhibition is an intermediator for AD-induced cognitive deficits and neurodegeneration. 3) To establish the role and timeline of proteasome dysfunction in AD patients and the translational potential of our proteasome-targeting interventions. Prior studies report impaired proteasome function in AD patients beyond that seen in age-matched controls. However, it is unclear if this impairment is a driver of pathogenesis or a product of disease progression. This investigation will use human tissue to establish where proteasome dysfunction occurs in the AD cascade and whether it co-varies with disease state, severity, symptom presentation, and biomarkers of the disease. This will establish the translational potential of our proteasome-targeting pharmacologic agents. If our investigations are successful, we will enhance mechanistic understanding of the role of the proteasome system ...