Focus areas
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. We also have shown that improving meningeal lymphatic drainage in the aged central nervous system leads to better glymphatic function and cognitive performance.
The lab is 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. We also are studying 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.
Research highlights
das Neves SP, Delivanoglou N, Ren Y, Cucuzza CS, Makuch M, Almeida F, Sanchez G, Barber MJ, Rego S, Schrader R, Faroqi AH, Thomas JL, McLean PJ, Oliveira TG, Irani SR, Piehl F, Da Mesquita S. Meningeal lymphatic function promotes oligodendrocyte survival and brain myelination. Immunity. 2024; doi:10.1016/j.immuni.2024.08.004.
Rego S, Sanchez G, Da Mesquita S. Current views on meningeal lymphatics and immunity in aging and Alzheimer's disease. Molecular Neurodegeneration. 2023; doi:10.1186/s13024-023-00645-0.
Da Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FG, Wall M, Jiang H, Dilip Kodira C, Alves de Lima K, Herz J, Louveau A, Goldman DH, Salvado AF, Onengut-Gumuscu S, Farber E, Dabhi N, Kennedy T, Milam MG, Baker W, Smirnov I, Rich SS, Dominantly Inherited Alzheimer Network, Benitez, BA, Karch CM, Perrin RJ, Farlow M, Chhatwal JP, Holtzman DM, Cruchaga C, Harari O, Kipnis J. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
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.
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.