Alleviating age-related memory impairment through proteasome stimulation

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Project Summary/Abstract Aging is characterized by a general decline in cognitive abilities, including the ability to accurately form and recall episodic memories. Age-related memory impairments affect nearly 25% of U.S. adults over the age of 65 and constitute a significant risk factor for the development of Alzheimer's disease (AD). The emotional and financial burden of aging on caregivers, family, and taxpayers is substantial and growing, as the projected percentage of the population of individuals 65 and older will increase from 4.1% to approximately 20% by 2050. A thorough understanding of the neurobiological factors that contribute to age-related cognitive decline will not only provide a mechanistic understanding of aging, but will also provide key avenues for therapeutics to minimize the negative effects of aging on memory and reduce risk for AD. Aging results in both impaired synaptic function in the hippocampus, a brain region critical for memory formation, and reductions in activity of the proteasome, the catalytic component of the ubiquitin-proteasome system (UPS) that controls most protein degradation in the brain. Decreased proteasome activity has been reported in aged tissue across organisms, including rodents and humans, and is associated with AD. Further, our group has provided strong evidence for a role of proteasome activity in memory formation and has collected preliminary data demonstrating that proteasome function is already decreased in middle-aged animals, before memory impairments are typically present. This suggests that proteasome downregulation precedes, and is likely a major contributing factor to, age-related memory impairments like those observed in AD. However, due to technical limitations, whether ameliorating these deficits in proteasome function can prevent or reverse age-related memory decline remains unknown. To address this gap in the field, we recently developed a novel CRISPR-dCas9 approach to persistently stimulate proteasome activity in specific brain regions of adult animals. Using this approach, the goal of this proposal is to test if increasing proteasome function in the hippocampus can ameliorate age-related memory impairments and associated pathophysiology. Aim 1 will test if increasing proteasome activity in the hippocampus of aged animals rescues age-related memory deficits, reduces neuroinflammation, and restores the normal learning-related degradation-specific proteome. Aim 2 will test if increasing proteasome activity in the hippocampus of young and middle-aged animals can prevent age-related memory deficits, increases in neuroinflammation, and dysregulation of the learning-related degradation-specific proteome at aged time points. Collectively, these results will provide critical insight into whether reversing proteasome dysregulation later in life or preventing proteasome dysfunction early in life can prevent or reverse age-related memory impairment.