DISSECTING THE INTERPLAY BETWEEN PROTEASOME DYSFUNCTION, PROTEOSTASIS AND ALZHEIMER'S DISEASE

Alzheimer's disease (AD) affects 5.5 million Americans producing cognitive deficits and mortality. Thereis no treatment for AD, thus, development of interventions to slow or reverse AD symptoms is a critical area ofresearch. Furthermore, AD is difficult to detect until substantial neurodegeneration has already occurred. Thisproposal investigates proteasome function both as an intervention to AD symptoms and as a tool for earlystage diagnosis in peripheral tissues. A key symptom of AD is proteostatic dysfunction. Patients as well asanimal models of AD have a pronounced decline in proteasome function. Using in vivo invertebrate and in vitrovertebrate models of AD, we have found that genetic and pharmacologic augmentation of proteasome delayscognitive and neurodegenerative symptoms, while reducing proteasome function accelerates AD progression. This proposal builds on the above exciting findings and is designed in response to RFA-AG-18-020,Role of Peripheral Proteostasis on Brain Aging and Alzheimer's Disease. The proposal has three goals.The first goal is to develop a mechanistic understanding of how proteasome dysfunction is linked toAD progression. We present, and test, two hypotheses to explain this interplay. The first hypothesis is that theproteasome has a key role in prevention of AD progression through degradation of ?-amyloid (A?) machineryand or its substrate (APP, BACE1, and ?-secretase activators, are all targets of proteasome degradation). Ifour results bear out, it would indicate that age-related declines in proteasome function result in a build-up ofthese proteins, which accelerates AD progression. The second hypothesis we test is if proteasome dysfunctiontriggered by A? inhibition drives downstream neurodegeneration rather than altering A? accumulation.Proteasome dysfunction on its own is shown to cause neurodegeneration and synaptic loss. If our findings areconsistent with this, it would indicate that proteasome dysfunction caused by A? inhibition is an intermediatorfor AD-induced cognitive deficits and neurodegeneration. The second goal is to test if AD triggersproteasome dysfunction in peripheral tissues as a diagnostic tool for early AD screening. We haveinitial findings supporting this. The third goal is to test if genetic or pharmacologic proteasomeaugmentation is a germane target for treatment of AD-like symptoms in mice that model AD. Theseexperiments are designed to advance us toward the long-term goal of developing novel screening tools andtreatments for AD in humans. This multi-PI project, led by a new investigator, seeks to develop a mechanisticunderstanding of the interplay between the proteasome and AD, test the efficacy of genetic and pharmacologicproteasome manipulation as an AD intervention, and test the viability of peripheral proteasome dysfunction asan early diagnosis tool. Our innovative models, state-of-the-art methods, expert investigative team, compellingpreliminary data, novel pharmacologics, new transgenic lines, and diverse biological systems increase thelikelihood of successfully achieving our goals and provide potential for clinical relevance.