Abstract
Neurodegeneration is a complex and multifaceted field, involving an array of neuronal and glial cell types. Neuronal death is central to this process and thought to be largely responsible for the onset of the clinical symptoms of neurodegeneration, whether this be in the context of Alzheimer’s Disease, Parkinson’s Disease, or Amyotrophic Lateral Sclerosis. Many other cell types, such as glia, previously thought to simply be scaffolding for neurons, have, in the last few decades, emerged as having active roles in both driving disease as well as potentially mitigating it. Research into myelin and oligodendrocytes in neurodegeneration is particularly nascent. Long thought to be simply purveyors of static insulation for the brain, oligodendrocytes have dynamic interactions with their neuronal partners. This is best exemplified at the axon-myelin interface. Myelin maintenance is a function of neuronal activity and metabolic needs. This relationship is not 1:1, however. Through their myelin sheaths, one oligodendrocyte maintains such connections with scores of neurons, positioning them as proverbial canaries in a coal mine for derangements in axonal metabolism and action potential firing.
Myelination is the central function of oligodendrocytes, and this process continues well into adulthood, ceasing in the prefrontal cortex at around age 30. While myelination may be the longest developmental process, it may also be among the first to decay with age. Even in healthy aging, white matter degeneration begins in middle age and become evident on imaging in the sixth decade of life. The extraordinary demand upon oligodendrocytes makes their development long and their degeneration swift. Most neurodegenerative disorders, and indeed normal aging, present with some level of demyelination. While demyelination is a pervasive feature across the spectrum of neurodegenerative disorders and not unique to Alzheimer’s disease, the potential for disease modification through targeted intervention upon this cell type remains largely unexplored in any neurodegenerative context.
This dissertation reviews the role of oligodendroglial cells in neurodegenerative disease, while drawing insights from their canonical and homeostatic functioning in development and in the healthy adult. The first part of my work in the lab investigates oligodendrocyte precursor cells (OPCs) dysfunction in Alzheimer’s Disease (AD), and how this may contribute to demyelination in a murine model of AD. We investigate how proteinopathy, notably accumulation of the extracellular chaperone, clusterin, in Alzheimer’s Disease inhibits differentiation of these precursor cells and thus affects myelination in our murine AD model.
The latter, main chapter of my work in lab focuses on the role of mature oligodendrocytes and the lineage overall in AD. We begin this investigation by performing transcriptional characterization of oligodendroglial cells in AD. We find that, in AD, while myelin as a physical structure declines, the production of myelin program-related transcripts, seemingly paradoxically, is increased as compared to normal aging. Some dysfunction may be inherent in this transcriptional upregulation, as we find an increase in DNA breaks in the promoter regions of myelin-associated genes in diseased samples, indicating transcriptional-related genomic stress. These processes were most apparent in preclinical disease, and overall transcriptional trends are largely shared with the 5XFAD model, which we use to model oligodendrocyte pathology in further studies. There is little compelling evidence of a significant decline in oligodendrocyte cell number in AD. We thus postulated that there is an alternate pathway, downstream of DNA damage, that may be affecting demyelination in the context of AD. We then investigated the role of the DNA damage sensing cGAS-STING pathway in oligodendrocytes in the 5XFAD model of AD. Interferon signatures are present in studies on oligodendrocytes in AD, as well as in our own sequencing performed on the 5XFAD model when isolating oligodendrocyte transcriptome. In this study, we selectively knock out Sting from oligodendroglial cells in the 5XFAD model and observe increased myelination, reduced plaque deposition and microgliosis as well as a significant improvement in spatial and learning memory, indistinguishable from WT controls. Overall, we introduce a novel pathway that underlies oligodendroglial dysfunction in AD and highlights the potential of this cell type to mitigate disease progression.
