ABSTRACT Normal human aging is characterized by cognitive impairments in executive function, learning and memory even in the absence of the neurodegeneration of Alzheimer's Disease (AD). While such cognitive aging was long believed to be due to neuronal loss, stereologic investigations of humans free of AD have shown that neurons are not lost, but instead myelin pathology increases and white matter is lost. The rhesus monkey is a valuable model of normal aging as they are spared the overt neurodegeneration of AD but still exhibit cognitive decline similar to humans. Examining the brains of cognitively assessed monkeys, we have found that the myelin shows splitting and ballooning of sheaths that likely impairs axonal conduction velocity and may lead to axon loss and reduced white matter volume. Importantly, myelin pathology correlates with age-related cognitive impairment in the monkey. While the mechanisms underlying this white matter pathology are still unknown, our lab has found that activation and phagocytic dysfunction of microglia increases in the white matter with age and correlates with cognitive decline. In pursuing this problem, I recently discovered that age-related increases in brain inflammation are accompanied by infiltration of peripheral T cells into the white matter in the same loci where myelin pathology is prevalent. These results challenge the concept that the brain is 'immune privileged' and instead might be vulnerable to infiltration of peripheral T cells leading to auto-attack and secondary inflammatory damage. Moreover, T cells do not infiltrate the aging gray matter, suggesting that infiltration is tissue specific and may play a role in age-related white matter pathology. The goal of this project is to determine why T cells infiltrate the aging brain and what their function is within in the white matter in parenchyma. I will perform a series of experiments on brain tissue from cognitively tested rhesus monkeys to test the hypothesis that age-related neuroinflammation leads to parenchymal infiltration of T cells where they are myelin-reactive and contribute to age-related myelin pathology. In Aim 1, I will explore how T cells are trafficked into the brain, what T cell subtypes are present and how T cells are related to myelin pathology. This will be accomplished using immunohistochemistry to label T cells and spectral confocal reflectance (SCoRe) microscopy to quantify myelin. In Aim 2, I will investigate the function of infiltrating T cells by analyzing their gene expression patterns using RNA sequencing and assessing their myelin reactivity and involvement in myelin sheath damage using organotypic slice cultures. To experimentally modulate T cell activity, the cultures will be treated with two therapeutics that target T cells and reduce damage to myelin in multiple sclerosis. In addition to characterizing brain parenchymal T cells with age, I will discover whether infiltrating T cells are myelin reactive and if they contribute to the white matter pathology and the severity of cognitive impairment. These data should identify targets for future experimental and therapeutic interventions to slow or prevent brain aging.

PROJECT NARRATIVE Normal aging is free of frank neurodegeneration and yet exhibits cognitive impairments that are likely due to white matter damage. It is well known that inflammation increases across the lifespan and we have found this correlates with white matter pathology and cognitive decline. We recently discovered a novel population of T cells that infiltrate the white matter with age and here propose to determine if they are autoreactive towards myelin and could be a causal or exacerbating factor in age-related myelin pathology and cognitive impairment.