Investigation of impaired neural stem cell activation in Alzheimer's Disease

PROJECT SUMMARY Alzheimer’s Disease (AD) is a devastating neurodegenerative disease that causes severe atrophy in the hippocampal area. The dentate gyrus of the mammalian hippocampus harbors populations of quiescent neural stem cells (NSCs) that can re-enter the cell cycle and differentiate into functional excitatory neurons. This process of neurogenesis supports learning and memory functions, as well as healthy mood regulation. However, in aging and AD, levels of neurogenesis sharply decline, and work in rodents has demonstrated a functional link between levels of neurogenesis and cognitive performance. Although quiescent NSCs are the source of new neurons, the current understanding of how these cells are impacted in AD is extremely limited. Preliminary work shows that quiescent NSCs are defective in a mouse model of AD. Moreover, these cells are particularly vulnerable to damage during aging, which is the greatest risk factor for AD. This proposal takes an integrated, multiomics approach to address the critical question of how the quiescent pool is affected in AD. Using a well-established mouse model and human tissue, specific Aim 1 will define the transcriptomic and epigenomic changes at the single cell level in AD. Work in Aim 2 will employ metabolomics to fully elucidate the metabolic changes that occur in AD. Lastly, Aim 3 will use a functional transcriptomics screen targeting central pathways in quiescent NSCs to identify how these cells are selectively vulnerable in AD. Together this work will result in a comprehensive understanding of how dormant NSCs are affected in a mouse model of AD as well as in human tissue. This study will provide key data to the neurodegeneration community that can be leveraged for functional studies and the development of interventions to prevent, treat and even cure neurodegeneration in the long term.