Aging is associated with cognitive decline, which frequently manifests pathologically as age-related dementia. The prevalence of dementia increases remarkably with advancing age, affecting nearly one out of three people over 85, and leads to dramatically reduced quality of life. There is currently no therapy for the efficient treatment of dementia, and new therapeutic strategies are critically needed. Our lab has pioneered the principle that a competent CD4+ T cells are required for proper cognitive behavior in mice. Therefore, T cell deficiency causes cognitive impairment; strikingly, this impairment is reversed when wild type T cells are injected into T cell deficient hosts. We have also shown that the meninges, a membranous structure which directly borders the brain, is the primary location through which T cells mediate their beneficial effects. Moreover, we showed that T cell-derived IL-4 is a key factor in the pro-cognitive molecular cascade. The current proposal is aimed to address key questions that remain yet unanswered: (1) how do T cells migrate into the meningeal spaces? (2) What are the precise effector cells in the meninges (and in the brain parenchyma) that respond to T cells and to their cytokines? (3) How does meningeal immune surveillance and function change with aging, and do these changes underlie age-associated cognitive decline? Decline in T cell function in aging (immunosenescence) is widely studied, and our results demonstrate a similar pattern of immune decline in the meninges of aging mice. We hypothesize that in aging, a decrease in meningeal IL-4 (due to reduced effector memory T cell function and increased regulatory T cells) will result in a pro-inflammatory skew of meningeal myeloid cells and of microglia, leading to cognitive decline. Therefore, boosting meningeal IL-4 or its downstream signaling could lead to development of feasible therapeutic interventions for age-associated cognitive decline. Three specific aims were designed to better elucidate the role of T cells within the meningeal spaces and their impact on age-associated cognitive decline and dementia. Specific aim #1 will determine the routes for T cell migration into the meninges; specific aim #2 will define the meningeal effector cells that respond to T cell-derived IL-4; specific aim #3 is a therapeutic aim wherein several approaches to boost healthy meningeal immunity-and thus improve cognitive function-are tested. We will address the proposed aims using novel transgenic animal models in conjunction with intravital two- photon imaging of the meninges and proximal brain parenchyma through a thinned skull, and state-of-the-art confocal imaging of whole mount meningeal preparations. Understanding how meningeal immunity is regulated in the steady state, and how T cells are migrating in and out of the meninges, is highly relevant not only to our understanding of the effect of T cells on learning behavior, but has broader implications on numerous neuroinflammatory conditions. Our findings have significant potential to uncover the etiology of and novel therapeutic targets for age-related dementia.
NIH ExPorter
NIH ExPorter