Characterizing Age-Related Differences in T cell Responses to Stroke

PROJECT SUMMARY Aging is the greatest risk factor for vascular dementia, the second most common cause of dementia after Alzheimer disease (AD). Vascular dementia comprises a large proportion of AD-related dementias, or ADRD. Vascular dementia is the result of poor vascular perfusion of the brain and can occur as a result of ischemic stroke, particularly in elderly individuals. The mechanisms underlying the greater risk of vascular dementia in elderly stroke patients are unclear thus limiting discovery of therapeutic approaches. Studies have shown a significant post-stroke inflammatory response in the aging ischemic brain that can persist and contribute to cognitive decline. However, the nature of this persistent immune response, particularly the adaptive T cell component, is not well characterized and the functions of brain-infiltrating T cells are not well established, especially in the context of aging. Therefore, this proposal will characterize late T cell responses to stroke in a mouse model of age-related post-stroke dementia. Aged stroke mice demonstrate a significant cognitive impairment that is accompanied by T cell infiltration in the post-stroke brain. As T cells undergo vast changes in immune repertoire and function with aging, it is likely that T cells that traffic to and reside in the post-stroke brain will have distinct functions that contribute to age-related differences in long-term stroke outcomes. This research proposal aims to (1) Use single cell T cell receptor and immune response gene sequencing to characterize infiltrating T cells in the aging ischemic hemisphere (Aim 1); (2) Utilize Seahorse bioenergetics, metabolomics, and T cell activation assays to identify age-related differences in T cell metabolism which fuel T cell activation and T cell function (Aim 2); (3) Test the extent to which excessive innate immune responses characteristic of aging stroke contribute to T cell-mediated cognitive decline, and determine the therapeutic potential of acutely inhibiting innate immunity to confer a more favorable adaptive immune response (Aim 3). Understanding how age-related changes in T cells contribute to chronic stroke outcomes will ultimately provide us with novel therapeutics for elderly patients of vascular dementia.