Mapping the crosslink of senescence and inflammation in neurodegeneration
Aim 1: Determine how and where senescence impacts microglial inflammatory profiles during neurodegeneration. I will determine: 1) how senescence impacts subpopulations of microglia and 2) explore senescent microglial spatial distribution. Aim 2: Define the senescence transcriptome in the human AD brain. To further understand the impact of microglial senescence in AD, I will extend these studies into postmortem human tissue. I will use human tissue to study the spatial transcriptomic distribution of senescent cells, including microglia, in tissue from AD patients and aged-matched controls.
Currently, there are only a few labs in the world that have employed MERFISH spatial transcriptomic technology. We have recently acquired one of the few systems that exist, which I implemented in the Schafer lab. Also, I have acquired mice in which I can induce cellular senescence in a cell type and temporal-specific manner. With these powerful approaches I am uniquely positioned to globally map senescence through all major central nervous system cell types. This will represent the first map of cellular senescence in the Alzheimer's disease brain. Microglia are now a major target for therapeutic intervention in (Alzheimer’s Disease) AD. While senescent cells, a hallmark of aging, have been identified in AD it remains unclear how senescent microglia contribute to neurodegeneration and whether senescence occurs uniformly through the whole brain or if is spatially restricted to specific brain regions more prone to neurodegeneration. I will now answer these key questions and I will likely also identify a wealth of new, senescence and microglia-specific molecules as future targets for therapeutic intervention in AD.