Role of meningeal lymphatic drainage in neurophysiology and brain function
The meningeal lymphatic vasculature plays a central role in central nervous system drainage and cleansing. We have shown that meningeal lymphatic outflow regulates fluid and macromolecule circulation within the brain's glymphatic system and that improving meningeal lymphatic drainage in the aged central nervous system leads to better glymphatic function and cognitive performance. The lab is currently assessing other aspects of brain physiology, such as lipid transport and metabolism, which might be affected in scenarios of reduced meningeal lymphatic outflow and result in altered brain function.
Meningeal lymphatics and neuroimmune interactions in neurological disorders
A growing body of evidence points to the involvement of the meningeal lymphatic system in the regulation of neuroimmune interactions not only at the brain-meningeal interface but also at the level of the brain parenchyma. In the lab, we are investigating the nature of the interactions between meningeal immune cells and lymphatic vasculature and how these interactions change with aging and impact brain drainage, neuroinflammation and disease progression in models of Alzheimer's disease, Parkinson's disease and frontotemporal dementia.
Alzheimer's disease risk factors and the meningeal lymphatic system
Aging is a main risk factor for different neurodegenerative disorders, including Alzheimer's disease. We have shown that the function of meningeal lymphatic vessels becomes progressively compromised with aging. Likewise, aging takes a major toll on resident immune cells of the brain and meningeal tissues. However, besides aging, there is very little evidence regarding the effects of other Alzheimer's disease risk factors on meningeal lymphatic drainage and immunity. We aim to explore if and how lifestyle factors, such as diet, and genetic factors, such as APOE4, induce long-lasting alterations in the meningeal lymphatic and immune systems.
Mechanisms of therapeutic regeneration of the meningeal lymphatic vasculature
Our studies show that meningeal lymphatic dysfunction affects neuroinflammation and neuropathology in models of Alzheimer's disease. Similar results were observed in other disease models such as traumatic brain injury and Parkinson's disease. In the lab, we will investigate the cellular and molecular mechanisms underlying meningeal lymphatic vessel regression and develop new methods to regenerate meningeal lymphatic vasculature, restore brain lymphatic cleansing and improve disease severity.
Alves de Lima K, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF, Smirnov I, Martelossi Cebinelli G, Mamuladze T, Baker W, Papadopoulos Z, Lopes MB, Cao WS, Xie XS, Herz J, Kipnis J. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nature Immunology. 2020; doi:10.1038/s41590-020-0776-4.
Da Mesquita S, Fu Z, Kipnis J. The meningeal lymphatic system: A new player in neurophysiology. Neuron. 2018; doi:10.1016/j.neuron.2018.09.022.
Louveau A, Herz J, Alme MN, Salvador AF, Dong MQ, Viar KE, Herod SG, Knopp J, Setliff JC, Lupi AL, Da Mesquita S, Frost EL, Gaultier A, Harris TH, Cao R, Hu S, Lukens JR, Smirnov I, Overall CC, Oliver G, Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nature Neuroscience. 2018; doi:10.1038/s41593-018-0227-9.
Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018; doi:10.1038/s41586-018-0368-8.
Louveau A, Da Mesquita S, Kipnis J. Lymphatics in neurological disorders: A neuro-lympho-vascular component of multiple sclerosis and Alzheimer's disease? Neuron. 2016; doi:10.1016/j.neuron.2016.08.027.