Project Summary/Abstract As the incidence of Alzheimer’s disease (AD) continues to increase and drugs targeting traditional disease etiology have thus far failed, it is critical to approach this devastating disease from different perspectives. Neural stem cells (NSC) have thus emerged as a potential therapeutic. Neural stem cells (NSCs) play a critical role in learning, mood, and memory by continuing to generate newborn neurons throughout life in the dentate gyrus of the hippocampus. This process of neurogenesis is impaired early in age and in Alzheimer’s disease. In addition, NSC numbers are correlated with AD outcome in humans and modulation of neurogenesis in mouse models can contribute to cognitive impairment or improvement. Thus, there remains a need to understand why NSC become dysfunctional and how to rejuvenate them for therapeutic use. To address these questions, we performed single-cell RNA sequencing upon young and old NSCs. We uncovered a gene network that older NSCs are unable to activate. Our lab discovered a compound predicted to activate this gene network and tested it in old mice. This compound can sustain high levels of NSC activation while increasing NSC pool size, neurogenesis, and cognition. These effects are unforeseen in NSC biology and reveal a novel regenerative capacity of NSCs without triggering depletion nor deepened quiescence. My preliminary data suggest that this drug uniquely targets a chromatin remodeling factor that is central in this identified gene network. Correlative evidence and existing literature further support this. Thus, I hypothesize that knockdown of this factor in young mice via lentivirus will recapitulate phenotypic effects of NSC aging (Aim 1) whereas overexpression of this factor is sufficient to promote NSC rejuvenation (Aim 2). This would provide support our compound works through targeting this factor and would establish mechanistic understanding of why NSCs decline in age and how to target them for rejuvenation in Alzheimer’s. The extensive use of immunohistochemistry, surgical techniques and associated computational training establish this project as an ideal training opportunity. This training plan incorporates acquisition of diverse skills in stem cell biology and neuroscience, specialized coursework in bioinformatics, the honing of presentation and writing skills, and career development that will help me achieve my goal of becoming a successful independent scientist in brain aging. My mentor, Dr. Michael Bonaguidi, has an exceptional training record and has been instrumental in the neurogenesis and NSC field. The Bonaguidi lab is located within the rapidly growing Broad Stem Cell Institute at USC, which is a highly collaborative and dynamic environment for my scientific development.