Many neurological disorders are associated with aging, the most prominent among them being Alzheimer?s disease (AD). Likewise, majority of neurological diseases, including AD, are also associated with dysfunction of the immune system. There are at least two unique aspects of central nervous system (CNS) physiology as it relates to neuro-immune interactions. First, the ?immune-privilege? status of the brain suggests that access of immune cells to the CNS parenchyma is restricted. Secondly, the parenchyma is devoid of lymphatic vessels. Recent findings from our lab have demonstrated that the meninges that envelop the brain harbors lymphatic vessels, and that this vasculature drains interstitial and cerebrospinal fluids, and therefore, serves the function of CNS-draining lymphatics. Moreover, unlike the parenchyma, the meningeal spaces are populated by a variety of immune cells, the activity of which has been linked to brain function, including learning and memory. Based on our preliminary and published results, we have put forward the overarching hypothesis that the age-related functional impairment of the meningeal lymphatics results in accumulation and aggregation of Ab (and potentially other proteins) within the meningeal spaces, triggering there a pro-inflammatory innate immune response, which underlies cognitive impairment. If this hypothesis is correct (and our preliminary data suggests so), then restoration/enhancement of drainage through meningeal lymphatics may remove aggregates from the meninges, halt meningeal pro-inflammatory immunity, and alleviate AD pathology and cognitive decline.
Our specific aims will address: (1) The impairment of meningeal lymphatics function and its underlying mechanism; (2) How impaired meningeal lymphatics correlate with pro-inflammatory skew of meningeal immunity; (3) Whether restoration of meningeal lymphatics function could revert the local pro-inflammatory response and ameliorate AD pathology. Addressing the aims of this proposal will shed a new light on the pathogenesis of AD and test the feasibility and efficacy of new, unexplored approaches to the alleviation of cognitive impairment associated with AD. The uniqueness of our approach allows us to intervene during the course of the disease, thereby acutely alleviating the symptoms. Altogether, our findings point to the hitherto unexplored meninges as a potential source of AD biomarkers and a target for therapeutic intervention. !

Public Health Relevance

Alzheimer?s disease (AD) is associated with aging and with dysfunction of the immune system, among other factors. CNS is an ?immune-privilege? organ and, therefore, there are no immune cells in the parenchyma. CNS parenchyma is also devoid of lymphatic vessels, but our lab has recently discovered lymphatic vessels in the meninges. These vessels serve the role of CNS drainage and their function is impaired with aging. We hypothesize that impaired lymphatics function would result in aggregation of meningeal Ab, triggering the immune response, which in turn may interfere with brain function. Our goal is to identify biomarkers in the CSF/meninges that correlate with early onset of cognitive impairment in AD and to target meningeal lymphatics therapeutically to slow down AD progression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Special Emphasis Panel (ZAG1)
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Mackiewicz, Miroslaw
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University of Virginia
Schools of Medicine
United States
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Da Mesquita, Sandro; Fu, Zhongxiao; Kipnis, Jonathan (2018) The Meningeal Lymphatic System: A New Player in Neurophysiology. Neuron 100:375-388
Da Mesquita, Sandro; Louveau, Antoine; Vaccari, Andrea et al. (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560:185-191
Kipnis, Jonathan (2018) Immune system: The ""seventh sense"". J Exp Med 215:397-398