UC Irvine

Neurodegeneration is a key feature of several neurological disorders and is characterized by systemic loss of neural structures and functions in the central nervous system. A diverse panel of environmental and heritable factors contribute to the development of neurodegen- erative phenotypes. Alzheimer’s disease, the most prevalent neurodegenerative disorder, is a complex polygenic disease that progressively alters the cellular and molecular makeup of the brain. A comprehensive understanding of these changes are necessary for developing future interventions and therapeutics to reverse the progression of disease or preventing it from ever occurring. In this dissertation, I leveraged several cutting-edge -omics technologies to generate high-quality molecular maps of the cell states that are dysregulated in AD. Fur- thermore, in-depth analysis of these maps have yielded numerous insights into the cellular phase of disease, especially regarding the relationship between genetics and cellular states. First, I used single-nucleus epigenomic and transcriptomic sequencing in postmortem human cortical tissue from late-stage AD donors and cognitively normal controls to deeply charac- terize changes in the gene regulatory landscape throughout disease. Next, I applied spatial transcriptomics to investigate changes with respect to amyloid pathologies in early-stage and late-stage AD, as well as AD in Down Syndrome. These studies led to numerous find- ings implicating a role for oligodendrocytes in neurodegeneration, thus prompting the final study. I leveraged mouse experiments where we used single-nucleus epigenomics and tran- scriptomics to track the molecular changes involved in remyelination, and to understand how the dynamics of oligodendrogenesis change with aging. Altogether, this dissertation provides foundational knowledge of gene-regulatory circuitry in neurodegeneration with cellular and spatial resolution.