Transcriptomic analyses of brain white matter in human neurodegenerative tauopathies

Abstract

Neurodegeneration is a debilitating process defining diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Research on neurodegeneration has focused on neuronal tau protein accumulation, which leads to progressive neurotoxicity. However, neurons are not the only culprit. Evidence now supports a role for non-neuronal glial cells in neurodegeneration. Indeed, glia-specific dysfunction may be key to the progression of neurodegeneration, perhaps more important than neurotoxicity alone. For this reason, my dissertation work has focused on investigating molecular and cellular differences in the glia-rich white matter of CTE, AD, and control postmortem human tissue. Results from this study may inform development of in-life disease diagnostics and therapeutic interventions. To evaluate molecular and cellular white matter changes in CTE, we applied single-nucleus RNA-seq and validation techniques to dorsolateral frontal white matter from individuals with mid-stage CTE versus matched controls. Results revealed striking differences in the glia of CTE compared to control. Oligodendrocytes appeared diminished in overall number and altered in relative proportions of subtypes, with a CTE oligodendrocyte population enriched for transcripts associated with cytotoxic iron accumulation. Overall numbers of astrocytes were indistinguishable between conditions but showed unexpected cell states, with one astrocyte subtype demonstrating elevated transcripts associated with neuroinflammation and aging in CTE. These findings support a role for glial cells in the pathogenesis of CTE. Our analyses of AD white matter were equally interesting and notably different from CTE. The transcriptomic findings suggest that late-stage AD white matter also contains fewer oligodendrocytes compared to controls, but those remaining did not show increased transcripts associated with iron storage, as in CTE. In AD, but not CTE, the overall number of astrocytes appeared to be greater than in controls, and like in CTE, they showed an elevation in transcripts associated with neuroinflammation and aging. Collectively, these findings highlight unique differences and similarities in brain white matter cells across two neurodegenerative tauopathies and control tissue samples. This foundational work, including the disease-specific findings, may serve as a starting point to improved diagnostic criteria for each disease. Moreover, this work highlights the importance of considering non-neuronal cellular and molecular alterations in neurodegenerative diseases.