Normal aging, even in the absence of neurodegenerative disease such as Alzheimer’s disease (AD), is still characterized by cognitive decline in the areas of learning, memory, processing speed, and executive function. Though initially believed to be due to neuronal loss, the root of cognitive decline in normal aging is now appreciated to be due to loss of white matter volume and accruing damage to insulating myelin sheaths that impairs axon conduction and leads to cortical disconnection. The causes of white matter disruption appear to be multifactorial and include oligodendrocyte dysfunction and increasing white matter neuroinflammation that together impede myelin homeostasis (i.e. maintenance and repair). Myelin damage leads to an accumulation of interstitial myelin debris that is normally phagocytosed by microglia. With age, microglia become ineffective at phagocytosis and clearance of myelin debris and become chronically reactive, secreting pro-inflammatory cytokines that perturb the processes underlying myelin maintenance and repair. However, it is unknown how these neuroinflammatory signals may call upon T cells of the adaptive immune system, which may also exacerbate myelin degradation and affect age-related cognitive decline. The overall goal of this dissertation work was to characterize the role that T cells may play in normal aging white matter dysfunction. To study the processes underlying normal aging, the rhesus monkey serves as a gold standard model due to similarity to humans in their extended lifespan, gray:white matter ratio, behavioral testing abilities, and development of age-related cognitive decline, in the absence of the confounds of AD pathology. Here, using immunohistochemistry on brains from behaviorally characterized monkeys, we demonstrate that CD3+ T cells in the perivascular space and within the parenchyma increase with age in the white matter but not the gray matter. In situ hybridization experiments showed that T cells express RNA for tissue entry (LFA1) but not for tissue egress (CCR7) suggesting that T cells actively enter the brain parenchyma. Further, T cell infiltration into the brain is correlated with the degree of microglial reactivity measured by morphologic density analysis of LN3-staining. These infiltrating T cells were predominantly CD8+ cytotoxic T lymphocytes, with a smaller percentage of CD4+ helper T cells present. The distribution of CD8+ T cells correlated with the distribution of CD4+ T cells as well as CD4+ microglia, suggesting a means for T cell reactivation upon entry into the white matter parenchyma. Single cell RNA sequencing in young versus aged white matter show that T cells in the old brain exhibit increased expression of genes involved in T cell activation and production of proinflammatory cytokines. The subset of proinflammatory microglia enriched in the aged brain are also enriched for gene pathways involved in activating T cells and inflammatory signaling. To explore the interaction between these two cell types, receptor ligand analyses were performed showing evidence that in the young brain, microglia are able to suppress T cell activation, but lose this interaction with age and instead gain an interaction which leads to the activation of T cells. Finally, beyond the myelin damage that cytotoxic CD8+ T cells can inflict directly, ligand receptor analysis revealed that in the old brain, oligodendrocytes may be promoting T cell activation via cytokine secretion. T cells may suppress myelination by blocking the FGFR2 receptor on oligodendrocytes. Together, these data provide convincing evidence that T cells enter the white matter parenchyma of the aging brain where they may be contributing to neuroinflammation, myelin damage, and attenuate myelin repair, and thus may be a novel therapeutic target with the goal of preventing or slowing cognitive decline associated with normal aging.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/43759 |
| Date | 01 February 2022 |
| Creators | Batterman, Katelyn V. |
| Contributors | Rosene, Douglas L. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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