Despite a high level of metabolic activity, the brain does not have a conventional lymphatic system to remove metabolites. The glia-lymphatic (glymphatic) system is a waste removal system that uses the perivascular space of the brain for fluid transport. The glymphatic system is a bulk flow system driven arterial pulsation and results in convective flow in the perivascular spaces. The glymphatic system is most active in the sleep state, where production of cerebrospinal fluid (CSF) is highest and the interstitial space is larger. Solutes as well as peptides such as amyloid beta can be transported in perivascular pathways by the glymphatic system and eliminated to the lymphatic vessels. Accumulation of proteins, such as amyloid beta, is a common feature of neurodegenerative diseases and we believe that the control of the glymphatic system could prevent or curb neurodegenerative diseases. Due to the recent discovery of the glymphatic system, many new discoveries are waiting to be made, including how to effectively manipulate the glymphatic system.
Astrocytes are the key regulators of brain homeostasis. Their endfeet processes ensheath the cerebral vasculature and contact thousands of synapses. We are interested in the endfeet of astrocytes, as they form perivascular pathways used by the glymphatic system for fluid transport. Aquaporin 4 (AQP4) water channels in the astrocyte endfeet are crucial for influx of cerebrospinal fluid (CSF) into the brain and clearance of solutes. Besides AQP4 molecular drivers of glymphatic flow remain elusive.
Similar to the lymphatic system, the glymphatic system connects to lymph nodes in the cervical region. Thus, there is a strong association between glymphatic and immune function. Fluid drains from the brain into meningeal lymphatic vessels, to the nasal mucosa via the cribriform plate, via spinal and cranial nerves, or simply perivenously. Drainage from the brain will mount an immune response in cervical lymph nodes. The idea of the brain being ‘immune privileged’ remains true in the sense that there are much fewer patrolling T cells in the brain e.g. than in the skin. However, meningeal lymphatic vessels and CSF efflux to cervical lymph via the nasal mucosa is understudied in relation to central nervous system immune function.
Principal investigator, Dr. Iben Lundgaard, is recipient of a Wallenberg Foundation starting grant. Over the next 4 years, this grant covers 2 PhD students, 2 postdocs plus technical support and also includes running costs and money for equipment.
Lund University was founded in 1666 and currently has 42,000 students. The Department for Experimental Medicine is a modern and vibrant place to work and study. The department counts 60 independent research groups and excellent core facilities. The Wallenberg Foundation has announced that they will fund 10 large starting grants in molecular medicine over the next few years to recruit new group leaders. One of these recruitments was Dr. Iben Lundgaard. The new research groups funded by the Wallenberg Foundation will stimulate the research environment and further expand the growing international environment at Lund University.
Principal investigator Iben Lundgaard has, during her Master degree in molecular biology, obtained experience from aging lab, Suresh Rattan, Na/K ATPase in Nobel laureate Jens Christian Skou's lab at University of Aarhus and apoptosis and calcium binding proteins in Martin Berchtold’s lab at University of Copenhagen. After a short internship in electrophysiology at University of Copenhagen, Iben started her PhD in the UK.
Iben Lundgaard did a PhD in neuroscience with Ragnhildur Thora Karadottir and Robin Franklin at University of Cambridge, UK, 2008-2012. The main findings of her PhD thesis were that growth factors neuregulin and BDNF interact with neuronal activity to control myelination and that remyelination after injury is dependent on NMDA receptors.
Dr. Lundgaard worked with Maiken Nedergaard at University of Rochester where the glymphatic system was discovered. During her time in the Nedergaard lab Dr. Lundgaard gained detailed knowledge on the glymphatic system, see for example the study on delivery of glucose from the CSF to the brain parenchyma via the glymphatic system. After 2 years, Dr. Lundgaard was promoted to assistant professor and stayed for another two and a half years to continue glymphatic research in multiple disease models. A number of projects from the Rochester lab are still on-going and will be continued in the new lab at Lund University.
The Lundgaard Lab is always interested in receiving applications from prospective students and postdocs.
Lundgaard I, Luzhynskaya A, Stockley J, Wang Z, Evans K, Swire M, Volbracht K, Gautier H, Franklin RJ, Ffrench-Constant C, Attwell D, Káradóttir R. (2013) Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes, Plos Biology 11(12):e1001743
Lundgaard I, Osório MJ, Kress BT, Sanggaard S, Nedergaard M. (2013) White matter astrocytes in health and disease, Neuroscience 276:161-73
Jessen N, Munk A, Lundgaard I, Nedergaard M. (2015) The glymphatic system – a beginner’s guide Neurochemical Research 40(12):2583-99
Lundgaard I, Li B, Xie L, Kang H, Sanggaard S, Haswell J, Sun W, Goldman S, Blekot S, Nielsen M, Takano T, Deane R, Nedergaard M. (2015) Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nature Communications 6:6807
Gautier H, Evans K, Volbracht K, James R, Sitnikov S, Lundgaard I, James F, Lao-Peregrin C, Reynolds R, Franklin R, Káradóttir R. (2015) Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors, Nature Communications 6:8518
Lundgaard I, Lu M, Yang E, Peng W, Mestre H, Hitomi E, Deane R, Nedergaard M. (2016) Glymphatic clearance controls state-dependent changes in brain lactate concentration Journal of Cerebral Blood Flow and Metabolism 37(6):2112-2124
Spitzer S, Volbracht K, Lundgaard I, Káradóttir R. (2016) Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease. Neuropharmacology 110(Pt B):574-585
Lundgaard I, Wang W, Eberhardt A, Vinitksy H, Reeves B, Peng S, Lou N, Hussain R, Nedergaard M. (2018) Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function. Scientific Reports 8 (1), 2246
Xavier A, Hauglund N, von Holstein-Rathlou S, Li Q, Sanggaard S, Lou N, Lundgaard I, Nedergaard M (2018). Cannula Implantation into the Cisterna Magna of Rodents. JOVE 135, e57378
Plog B, Mestre H, Olveda G, Sweeney A, Kenney HM, Cove A, Dholakia K, Titho J, Nevins T, Lundgaard I, Du T, Kelley D, Nedergaard M. (2018) Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI Insight 2018;3(20):e120922
Ramos R, Bèchet NB, Battistella R, Pavan C, Xavier ALR, Nedergaard M, Lundgaard I. (2019) Cisterna Magna Injection in Rats to Study Glymphatic Function. Methods Mol Biol. 1938:97-104
Mestre H, Kress B, Zou W, Pu T, Murlidharan G, Rivera R, Simon M, Pike M, Plog B, Xavier A, Thrane A, Lundgaard I, Thomas J, Xiao M, Asokan A, Iliff J, Nedergaard M. (2017) Aquaporin-4 dependent glymphatic solute transport in rodent brain. eLife 2018;7:e40070
Munk AM, Wang W, Bèchet NB, Cheng AX, Eltanahy A, Sigurdsson B, Benraiss A, Mäe MA, Kress BT, Kelley DH, Betsholtz C, Møllgård K, Meissner A, Nedergaard M, Lundgaard I. (2019) Development of the glymphatic system is dependent on PDGF-B signaling. Cell Reports 26 (11), 2955-2969. e3
Mohanty T, Fisher J, Bakochi A, Neumann A, Cardoso J, Karlsson C, Pavan C, Lundgaard I, Nilson B, Reinstrup P, Bonnevier J, Cederberg D, Malmström J, Bentzer P, Linder A. (2019) Neutrophil extracellular traps in the central nervous system: a novel therapeutic target in pneumococcal meningitis. Nature Communications 10(1):1667.
Reeves BC, Karimy JK, Kundishora AJ, Mestre H, Cerci HM, Matouk C, Alper SL, Lundgaard I, Nedergaard M, Kahle KT. Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus. Trends Mol Med. 2020 pii: S1471-4914(19)30299-0.
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