White matter alterations in chronic traumatic encephalopathy
Chancellor, Sarah Elizabeth
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The diagnostic lesions of neurodegenerative tauopathies, such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD), are located in the cortex, however, white matter pathology is a contributing factor to neurodegeneration. At all stages of disease, white matter axonal and glial morphological abnormalities are present in CTE. Similarly, white matter changes may emerge before cortical pathology in AD. White matter irregularities bear functional consequences, as they are associated to some of the most common and onerous symptoms of these diseases, like cognitive deficits and depression. Individuals with AD present with both reduced white matter integrity and cognitive symptoms starting early in disease progression. In CTE, which is triggered by repetitive head impacts (RHI), individuals are particularly vulnerable to white matter damage as RHI exposure alone is sufficient to injure white matter tracts and induce depression symptoms. In this dissertation, I investigated the cellular and molecular presentation of white matter glial cells, including astrocytes, oligodendrocytes (OLs), and microglia in CTE and AD as compared to controls. To investigate white matter pathology, I examined glial cells on a cellular level. Neuropathologically-verified CTE samples were compared to RHI-experienced controls, with both groups containing samples with and without depressed mood. CTE with depressed mood had reduced myelin and increased neuroinflammatory peripheral cells compared to non-depressed CTE and contained increased numbers of microglia compared to non-depressed CTE and control samples. Using single-nucleus transcriptomics in neuropathologically-verified CTE samples compared to matched RHI-naïve controls, OL loss, iron aggregates, OL iron trafficking dysregulation, and two distinct astrocyte subpopulations were detected in CTE white matter. AD white matter, compared to the same control samples in the same brain region, was also depleted of OLs by single-nucleus transcriptomics. However, OLs did not demonstrate iron-related transcriptional profile like those in CTE and, in further contrast, displayed increased numbers of microglia and astrocytes. Together, these findings implicate previously uncharacterized white matter glia in the neurodegenerative process of CTE and AD and further elucidate the etiology of neurodegeneration-related symptoms in CTE. These findings may aid in the development of therapeutics targeting glial contributions to the pathologic processes of both CTE and AD.
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