Neural stem cell rejuvenation through single cell pharmacogenomics

PROJECT SUMMARY Age is the major risk factor for most chronic human diseases, including Alzheimer’s disease (AD). Neural stem cells (NSCs) are particularly vulnerable to cellular aging and undergo functional decay in the mature brain. As a result, adult neurogenesis and its contributions to memory in health and AD are compromised at early ages. A central goal in regenerative medicine for AD is to determine the factors that rejuvenate endogenous NSCs and augment cognition. Yet, NSCs are commonly perceived to be a poor target for anti- aging interventions. A daunting challenge remains for NSC rejuvenation: to restore older NSC proliferation, increase their numbers, alter NSC fate for neurogenesis and sustain these changes. Systems biology offers a potential solution by integrating information from multiple fields. We propose to develop computational network and pharmacogenomics approaches to prioritize and modulate key age-related changes for NSC rejuvenation. Our prior work utilized single cell transcriptomics to define molecular cascades that initiate adult neurogenesis and are compromised during aging. Preliminary data now identifies a new transition signature that distinguishes quiescent from active NSCs and is altered with age. Our new single cell pharmacogenomics approach utilizes the transition signature to identify a compound that rejuvenates NSC function by expanding the NSC pool, increasing neurogenesis and sustaining NSC proliferation. Animal behavioral studies also demonstrate improved cognition in older mice. Thus, data detailed in this proposal strongly suggests we can apply combined “omics” approaches to reprogram older NSC function and provide a new understanding of adult neurogenesis in aging. The mechanisms mediating this NSC reprogramming remain enigmatic. We will advance the new pharmacogenomics with systems biology techniques in network connectivity and co-expression to prioritize mechanisms by which NSC aging is reversed (Aim 1), older NSC function is augmented (Aim 2) and how these changes are sustained (Aim 3). Together, this study will reveal evidence of NSC rejuvenation and demonstrate proof-of-principle utility of new single cell pharmacogenomics and gene networks for enhancing neurogenesis in the aged hippocampus. These results would provide a paradigm shift in NSC capacity for regeneration, as well as mechanistic insight into NSC vulnerability to aging, resilience to their decline, and building cognitive reserve.