Faculty Opinions recommendation of Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.

Aging is a major risk factor for many neurological pathologies and the mechanisms underlying brain aging remain elusive.Unlike other tissues, the central nervous system (CNS) parenchyma is devoid of lymphatic vasculature and removal of waste products is performed mainly through a paravascular route.(Re)discovery and characterization of meningeal lymphatic vessels prompted for an assessment of their role in CNS waste clearance.Here we show that meningeal lymphatics are draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes.Impairment of meningeal lymphatic function slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment.Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance.Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease (AD) promotes amyloid deposition in the meninges, which closely resembles human meningeal pathology, and aggravates parenchymal amyloid accumulation.Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline.Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.The CNS has been for decades referred as an immune privileged organ 1 , due to its limited interaction with the immune system, especially under homeostatic healthy conditions 2,3 .Although immune cells do not enter the parenchyma of the healthy brain, their surveillance of the CNS takes place within the meningeal spaces, where a great variety of immune cells is found 2,3 .Our group along with others 4,5 , have recently (re)discovered and characterized the lymphatic vessels within the meninges (of rodents 4 , non-human primates and humans 6 ), although the role of these vessels in CNS function and in pathologies remains elusive.Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network.In contrast, the parenchyma of the CNS is devoid of lymphatic vasculature 2 ; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (Aβ) peptides, is mediated by a combination of transcellular transport mechanisms across the blood-brain and blood-cerebrospinal fluid (CSF) barriers [7][8][9] , phagocytosis and digestion by resident microglia and recruited monocytes/macrophages 10,11 , and CSF influx and ISF efflux through a paravascular (glymphatic) route [12][13][14] .The (re)discovery and characterization of meningeal lymphatic vessels prompted for a reassessment of the pathways of CNS waste clearance 4,5 .The role of this vasculature in brain function, specifically in the context of aging and AD, has not been studied.AD is the most common form of dementia and its prevalence increases with age 15,16 .Extracellular deposition of Aβ aggregates, the main constituent of senile plaques, is considered a pathological hallmark of AD that contributes to neuronal dysfunction and behavioral changes 16,17 .It is interesting to note that Aβ protein was initially isolated from homogenates of meningeal tissue from AD patients 18 .However, the mechanisms underlying the accumulation of Aβ in the AD brain and meninges are still not fully understood.Aging-associated decrease of paravascular recirculation of CSF/ISF 13 is thought to be responsible, at least in part, for the accumulation of Aβ in the brain parenchyma 12,13,19 .Aging also leads to progressive lymphatic vessel dysfunction in peripheral tissues [20][21][22] .However, little is known about a possible functional