Antoine Louveau, PhD
Assistant Staff
Assistant Professor, Molecular Medicine, CCLCM-CWRU
Email: [email protected]
Location: Cleveland Clinic Main Campus
Research
What happens at the borders of your brain matters for your health. The Louveau lab studies the critical boundaries that surround and protect the brain—including the protective layers of the meninges and skull, the blood-brain barrier that controls what enters the brain, and the choroid plexus that produces spinal fluid. These borders play crucial roles in brain development, function, and aging.
We used to think the immune system only caused problems for the brain. Now we know the relationship is far more complex—the brain actually needs the immune system to work properly. Most of this communication happens right at the brain's borders, where the nervous system meets the rest of the body. When these borders don't work correctly, virtually every brain disorder—from developmental conditions to neurodegenerative disease—is affected.
Our lab uses laboratory models and human tissue samples to answer three key questions: 1) How do the brain's borders malfunction in different diseases? 2) Can we prevent or slow disease by targeting these borders? 3) Can we develop new treatments that restore normal border function?
Biography
Dr. Antoine Louveau is an Assistant Staff member in the Department of Neurosciences at Cleveland Clinic's Lerner Research Institute and holds faculty appointments at Case Western Reserve University and Kent State University. He earned his Ph.D. from the University of Nantes in France in 2013, where he studied the role of immune molecules in neuronal development and plasticity. Dr. Louveau completed his postdoctoral training at the University of Virginia (2014-2018), where he made a groundbreaking discovery that reshaped our understanding of brain immunity. His 2015 Nature publication revealing functional lymphatic vessels in the central nervous system challenged the long-held belief that the brain lacks a classical lymphatic drainage system, fundamentally changing how we view neuroimmune interactions.
Since establishing his independent laboratory at Cleveland Clinic in 2018, Dr. Louveau has pioneered research on how the brain's border systems—including meningeal lymphatics, the blood-brain barrier, and choroid plexus—regulate brain function in health and disease. His work spans neurodevelopmental disorders, neurodegeneration, and neuroimmune diseases, with current NIH funding supporting investigations into lymphatic dysfunction in autism spectrum disorders and integrin regulation of vascular function in Alzheimer's disease. Dr. Louveau has authored over 25 peer-reviewed publications in leading journals including Nature, Nature Neuroscience, Neuron, and Journal of Experimental Medicine. He serves on multiple NIH and international grant review panels and is an active member of six professional societies. Through his laboratory, he has mentored over 25 undergraduate, graduate, medical, and postdoctoral trainees, fostering the next generation of neuroimmunology researchers.
Education & Professional Highlights
"CIMER Trained Mentor" indicates the principal investigator has completed mentorship training based on curriculum from the Center for the Improvement of Mentored Experiences in Research, aimed at advancing mentoring relationships and promoting cultural change in research.
Education and Professional HighlightsEducation:
- Ph.D., University of Nantes, France, 2013
- Master of Sciences, University of Nantes, France, 2010
- Bachelor of Sciences, University of Nantes, France, 2008
Training:
- Postdoctoral Research Associate, University of Virginia, 2014-2018
Professional Highlights:
- Assistant Staff, Department of Neurosciences, Cleveland Clinic Lerner Research Institute, 2018-present
- Assistant Professor, Department of Molecular Medicine, Case Western Reserve University, 2019-present
- Principal Investigator, NIH R01 grant studying lymphatic dysfunction in neurodevelopmental disorders
- Principal Investigator, NIH R56 grant investigating integrin regulation of vascular function in Alzheimer's disease
- Published landmark discovery of meningeal lymphatic vessels in Nature (2015), fundamentally changing understanding of brain immunity
- Author of 25+ peer-reviewed publications in leading journals including Nature, Nature Neuroscience, Neuron, and Journal of Experimental Medicine
- Grant reviewer for NIH, European Research Council, and French National Research Agency
- Member, Society for Neuroscience, American Association of Immunologists, International Society of Neuroimmunology
Awards and Recognition:
- LE&RN Young Investigator Conference Scholarship, 2016
- Best Oral Presentation, French Club of Neuro-Immunology, 2011
- Postdoctoral Research Day Poster Award, University of Virginia, 2015
Research
Research OverviewIn the Louveau lab, we study the critical role of the brain and spinal cord borders—particularly the meninges and skull—in both normal physiological conditions and disease states. Unlike the brain parenchyma, which remains virtually devoid of immune cells except for resident microglia under healthy conditions, the meninges harbor a remarkably rich and dynamic immune environment. This meningeal immune landscape is uniquely sustained by dual sources: the peripheral blood vasculature and the local skull bone marrow. The meninges also contain a functional network of lymphatic vessels that actively drain cerebrospinal fluid, metabolic waste products, and immune cells away from the central nervous system. Our previous work demonstrated that disruption of these meningeal lymphatic vessels profoundly affects the development and progression of neurological disorders including multiple sclerosis and Alzheimer's disease.
The meninges constitute a complex structure strategically positioned at the critical interface between the peripheral immune system and the brain parenchyma. Despite their importance, fundamental questions remain: How is the meningeal compartment formed and maintained? How do changes in the meningeal environment influence both normal brain function and disease? Our laboratory addresses these questions through three interconnected research programs.
1. The Role of the Meningeal Compartment in Neurodevelopmental Disorders
We have observed extensive remodeling of both the meningeal immune compartment and meningeal lymphatic vasculature during critical windows of normal postnatal brain development. Remarkably, this developmental process appears to be significantly disrupted in neurodevelopmental diseases—it may be blunted in conditions like autism spectrum disorders, pathologically altered in Fragile X syndrome, or aberrantly expanded in inflammatory neurodevelopmental conditions.
Our research program investigates four fundamental questions: First, we seek to identify what local factors (neuronal activity, immune signals, vascular-derived factors) and peripheral factors (metabolic health, early-life stress, microbiome, systemic inflammation) regulate the development and maintenance of the meningeal compartment during critical developmental periods. Second, we investigate the mechanisms by which neurodevelopmental diseases lead to alterations of the meningeal compartment—do genetic mutations directly affect meningeal cells, or does abnormal neuronal activity send aberrant signals to the meninges? Third, we examine how manipulating the developing meningeal lymphatic vasculature impacts disease progression and core behavioral symptoms. We employ targeted genetic, pharmacological, and surgical approaches to enhance or impair meningeal lymphatic function during specific developmental windows. Fourth, we are actively testing novel therapeutic approaches that target the meningeal compartment to improve core symptoms of neurodevelopmental diseases, including pharmacological agents that enhance lymphatic function and strategies that modulate meningeal immune responses.
2. Integrin Regulation of the Blood-Brain Barrier in Neurodegeneration
Recent unbiased proteomic analyses from human Alzheimer's disease tissue have highlighted the fundamental roles of vascular dysfunction and extracellular matrix remodeling in disease pathogenesis. Integrins—transmembrane receptors that mediate cell-extracellular matrix interactions—have emerged as critical regulators of vascular function at the blood-brain barrier. We focus on integrins expressed by brain endothelial cells, pericytes, astrocytes, and vascular smooth muscle cells, investigating how integrin-mediated signaling controls vascular integrity, permeability, immune cell trafficking, and clearance of toxic proteins.
Our integrin-focused research addresses four questions: First, we investigate how neurodegenerative conditions lead to alterations in integrin expression, localization, and activation at the vasculature using single-cell sequencing, spatial transcriptomics, and functional proteomics in both mouse models and human tissue. Second, we interrogate how changes in integrin function contribute to both vascular and pathological features of neurodegeneration, including blood-brain barrier breakdown, impaired cerebral blood flow, and accumulation of amyloid plaques. Third, we aim to molecularly characterize new functions of integrins at the blood-brain barrier beyond their classical adhesion roles, employing proteomics and functional assays to identify novel integrin-interacting proteins and signaling pathways. Fourth, we are developing therapeutic strategies to modulate vascular integrin function in neurodegeneration, including small molecules and biologics, and assessing whether these approaches can restore barrier integrity, improve cerebral perfusion, and preserve cognitive function.
3. The Skull Bone Marrow/Meningeal Axis as a Neuroprotective Strategy
The skull bone marrow serves as a local reservoir of immune cells that can directly access the meninges and brain through specialized channels in the skull bone. Recent studies suggest that myeloid cells originating from skull bone marrow may exhibit more neuroprotective and less inflammatory phenotypes compared to their peripheral counterparts, suggesting this axis could be harnessed therapeutically.
Our research pursues two major directions: First, we are investigating the molecular mechanisms that regulate cell migration from skull bone marrow to the central nervous system. What chemokines and signals attract these cells? What anatomical routes do they take? What distinguishes skull bone marrow-derived cells from peripherally-derived counterparts? We use advanced imaging, fate-mapping strategies, and single-cell transcriptomics to map the journey and characterize the unique molecular signatures of these cells. Second, we are interrogating the therapeutic potential of skull bone marrow-derived cells in preclinical models of neurological diseases. Can we enhance the neuroprotective properties of endogenous skull bone marrow cells? Can we engineer these cells to deliver therapeutic molecules? We are testing these approaches in models of stroke, traumatic brain injury, multiple sclerosis, Alzheimer's disease, and neurodevelopmental disorders to determine whether this represents a viable therapeutic strategy.
Through these integrated research programs, we aim to advance understanding of how the brain's border systems regulate neural function and translate these insights into novel therapeutic interventions for neurological disorders that currently lack effective treatments.
Our Team
Selected Publications
Tavares GA, Louveau A. (2021) Meningeal Lymphatics: An Immune Gateway for the Central Nervous System. Cells 10(12):3385. PMID: 34943894; PMCID: PMC8699870
Da Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FG, Wall M, Jiang H, Kodira CD, de Lima KA, Herz J, Louveau A, Goldman DH, Salvador 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. (2021) Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature 593(7858):255-260. PMID: 33911285; PMCID: PMC8817786
Frederick N, Louveau A. (2020) Meningeal lymphatics, immunity and neuroinflammation. Curr Opin Neurobiol. 62:41-47. PMID: 31816570
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. (2018) CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 21(10):1380-1391. PMID: 30224810
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. (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560(7717):185-191. PMID: 30046111
Cronk JC*, Filiano AJ*, Louveau A, Marin I, Marsh R, Ji E, Goldman DH, Smirnov I, Geraci N, Acton S, Overall CC, Kipnis J (2018) Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J Exp Med. 215(6):1627-1647. PMID: 29643186; PMCID: PMC5987928
Louveau A, Filiano AJ, Kipnis J. (2018) Meningeal whole mount preparation and characterization of neural cells by flow cytometry. Curr Protoc Immunol. 121(1). PMID: 30008983
Louveau A. (2018) Meningeal Immunity, Drainage, and Tertiary Lymphoid Structure Formation. Methods Mol Biol. 1845:31-45. PMID: 30141006
Herz J, Louveau A, Da Mesquita S, Kipnis J. (2018) Morphological and Functional Analysis of CNS-Associated Lymphatics. Methods Mol Biol. 1846:141-151. PMID: 30242757
Louveau A, Kipnis J. (2018) Sex, Gut, and Microglia. Dev Cell 44(2):137-138. PMID: 29401417
Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. (2017) Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife 2017 Oct 3;6. PMID: 28971799; PMCID: PMC5626482
Louveau A*, Plog BA*, Antila S*, Alitalo K, Nedergaard M, Kipnis J. (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 127(9):3210-3219. PMID: 28862640; PMCID: PMC5669566
Jung E, Gardner D, Choi D, Park E, Jin Seong Y, Yang S, Castorena-Gonzalez J, Louveau A, Zhou Z, Lee GK, Perrault DP, Lee S, Johnson M, Daghlian G, Lee M, Jin Hong Y, Kato Y, Kipnis J, Davis MJ, Wong AK, Hong YK. (2017) Development and Characterization of A Novel Prox1-EGFP Lymphatic and Schlemm's Canal Reporter Rat. Sci Rep. 7(1):5577. PMID: 28717161; PMCID: PMC5514086
Cronk JC, Herz J, Kim TS, Louveau A, Moser EK, Sharma AK, Smirnov I, Tung KS, Braciale TJ, Kipnis J. (2017) Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice. JCI Insight 2(2):e88257. PMID: 28138553; PMCID: PMC5256138
Cisternas P, Louveau A, Bueno SM, Kalergis AM, Boudin H, Riedel CA. (2016) Gestational Hypothyroxinemia Affects Glutamatergic Synaptic Protein Distribution and Neuronal Plasticity Through Neuron-Astrocyte Interplay. Mol Neurobiol. 53(10):7158-7169. PMID: 26687181
Louveau A*, Da Mesquita S*, Kipnis J. (2016) Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer's Disease? Neuron 91(5):957-973. PMID: 27608759; PMCID: PMC5019121
Raper D*, Louveau A*, Kipnis J. (2016) How Do Meningeal Lymphatic Vessels Drain the CNS? Trends Neurosci. 39(9):581-586. PMID: 27460561; PMCID: PMC5002390
Louveau A, Nerrière-Daguin V, Vanhove B, Naveilhan P, Neunlist M, Nicot A, Boudin H. (2015) Targeting the CD80/CD86 costimulatory pathway with CTLA4-Ig directs microglia toward a repair phenotype and promotes axonal outgrowth. Glia 63(12):2298-312. PMID: 26212105
Louveau A. (2015) Cerebral lymphatic drainage: implication in the brain immune privilege. Med Sci (Paris) 31(11):953-6. PMID: 26576598
Louveau A, Harris TH, Kipnis J. (2015) Revisiting Revisiting the Mechanisms of CNS Immune Privilege. Trends Immunol. 36(10):569-577. PMID: 26431936; PMCID: PMC4593064
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337-41. PMID: 26030524; PMCID: PMC4506234
Louveau A, Angibaud J, Haspot F, Opazo MC, Thinard R, Thepenier V, Baudouin SJ, Lescaudron L, Hulin P, Riedel CA, Boudin H. (2013) Impaired spatial memory in mice lacking CD3ζ is associated with altered NMDA and AMPA receptors signaling independent of T-cell deficiency. J Neurosci. 33(47):18672-85. PMID: 24259588
Angibaud J, Baudouin SJ, Louveau A, Nerrière-Daguin V, Bonnamain V, Csaba Z, Dournaud P, Naveilhan P, Noraz N, Pellier-Monnin V, Boudin H. (2012) Ectopic expression of the immune adaptor protein CD3zeta in neural stem/progenitor cells disrupts cell-fate specification. J Mol Neurosci. 46(2):431-41. PMID: 21809042
Angibaud J*, Louveau A*, Baudouin SJ, Nerrière-Daguin V, Evain S, Bonnamain V, Hulin P, Csaba Z, Dournaud P, Thinard R, Naveilhan P, Noraz N, Pellier-Monnin V, Boudin H. (2011) The immune molecule CD3zeta and its downstream effectors ZAP-70/Syk mediate ephrin signaling in neurons to regulate early neuritogenesis. J Neurochem. 119(4):708-22. PMID: 21895656