Immune system supports brain function

Aging is associated with cognitive decline, which can manifest pathologically as age-related dementia. Aging is also the major risk factor for the development of Alzheimer’s disease. There is currently no effective treatment for age-associated dementia and no therapies for Alzheimer’s disease. Challenges associated with brain disorders include a lack in understanding of the underlying mechanisms and poor accessibility of the brain due to the blood-brain barrier. Over the last decade, we have been studying meningeal spaces and their relevance to brain function. Our long-standing interest in the meninges and its role in brain function has led us to characterize meningeal lymphatic vessels and to observe many intriguing changes in meningeal immunity with age, and accordingly to raise the questions: are meningeal immune and lymphatic alterations relevant to age- related cognitive decline? If so, could meningeal lymphatic vasculature or meningeal immunity be therapeutically targeted to alleviate age-related dementia and/or Alzheimer’s disease? Here, we are proposing to test our overall hypothesis, that age-related impairment in meningeal lymphatic function results in impaired meningeal blood vasculature (presumably through build-up of waste products), collectively leading to abnormal meningeal immunity, which subsequently results in age-associated impairment of cognitive function. We propose that improving meningeal lymphatic function (or directly targeting the immune system and/or its soluble mediators) may be a plausible therapeutic approach for age-associated cognitive decline. Three specific aims were designed to elucidate the role of meningeal vasculature and immunity in age-associated cognitive decline, dementia, and mouse models of Alzheimer’s disease using state-of-the-art imaging, surgical and pharmacological techniques in mice, as well as a validation of select findings in human dura specimens from fresh autopsies. Specific aim #1 will establish whether dysfunction of meningeal lymphatics may exacerbate the aging phenotype of meningeal blood vasculature; specific aim #2 will define the changes occurring in meningeal immune cells upon vascular dysfunction; specific aim #3 is a therapeutic aim wherein several approaches to boost healthy meningeal immunity—and thus improve cognitive function—will be tested. Understanding how meningeal vasculature and immunity are changing with age and in diseases, such as Alzheimer’s disease, has broad implications in numerous neurological conditions associated with aging. Our findings, therefore, have significant potential to uncover the etiology of and identify novel therapeutic targets for age-related dementia and Alzheimer’s disease. !