Research

Brain-wide clearance system - the glymphatic system

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.

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Preprints! Get the latest of our work here:

Glymphatic function in the gyrencephalic brain

An Improved Method for Physical Separation of Cerebral Vasculature and Parenchyma Enables Detection of Blood-Brain-Barrier Dysfunction.

Watch our 3-year anniversary lab video!

The cleaning system of the brain

Astrocytes

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.

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Neuroimmunology

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.

The Lab

The Lundgaard Lab was founded in 2017 by a starting grant from the Knut & Alice Wallenberg Foundation. The lab is part of the Wallenberg Centre for Molecular Medicine (WCMM) at Lund University which is a multi-disciplinary Centre that stimulates interactions between clinicians and pre-clinical researchers.

Lund University

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.

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Iben Lundgaard

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Iben Lundgaard, PhD. Iben is a non-obligate vegetarian (Christmas roast and paté excluded), from Svendborg, Denmark. She likes cats, studying brains and learning about medical research. Her favorite TV show is ‘The Bridge’. Likes asking Swedes whether the town Lund was founded by the Danes, pretending to not already know the answer. Her dream is to cure Alzheimer’s disease by targeting the glymphatic system. The name Iben is derived from the word ‘ibenholt’ which means ebony in Danish.

Early Career

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.

PhD

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 glutamate receptors.

Postdoctoral training

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.

Lab members

Roberta Battistella

Roberta Battistella, PhD student (3rd year). Roberta was the first to join the lab. She is from a sunny coastal town in Italy not so dissimilar to Lund. She is interested in how the glymphatic system is affected in Parkinson’s disease. Roberta likes espresso and is a master of stereotaxic injections. In her free time, she likes to grow plants from seeds and keep them alive in the challenging Swedish climate. You can make Roberta’s ears bleed if you talk about putting pineapple on the pizza.

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Nicholas Bèchet

Nicholas Bèchet, PhD student. Nic is from South Africa but also spent a few years in the Netherlands before moving to Sweden. He has a BSc in Medicine and MSc in Neuroscience and currently works on light sheet imaging of the glymphatic system, in both rodent and pig brains. Nic enjoys cooking as well as spending time on physical health and is passionate about his African heritage. Nics goal here in Lund is to develop new techniques and model systems to better understand fundamental glymphatic physiology and translate this knowledge from animals to humans. Fun fact: Nic is a 3rd generation South African but has a diverse family heritage including Irish, Welsh, English, Scottish, Danish and Mauritian ancestors. Nics favorite pastime is hanging out in tattoo parlors.

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Marta Ramos

Marta Ramos, PhD student. Marta is from Spain and prior to her arrival to Lund, she served as research assistant in labs all over the world, including Australia, Malta and France. Marta holds a BSc in Biotechnology and MSc in Neuroscience and is interested in neuroinflammation as well as imaging & visualization techniques. Marta specializes in neuroinflammatory diseases with a focus on the glymphatic system but sometimes also draws beautiful illustrations for our scientific publications. Marta is a member of the Medical Doctoral Student Council, where she serves as the representative of the council in the Lund Doctoral Student Union, which represents all PhD students in the university. Marta is learning Swedish and some computer programming on the side. In her free time, she also enjoys training Brazilian Jiu-jitsu. Interestingly, Ramos means ‘branches of the perivascular tree’ in Spanish.

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Tekla Kylkilahti

Tekla Kylkilahti, MD-PhD student. (1st year) Tekla hails from Finland, so winter in Lund feels like a summer holiday to her! Tekla has a BSc in Anatomy and Developmental Biology from King’s College London and a MSc in Molecular Biology from Lund University. Her favourite pastime is shocking people with her transparent optically cleared mice and scanning her friends with the 7 Tesla MRI. When Tekla isn’t studying CSF flow or attending med school classes, you’ll probably find her playing tennis, dancing ballet or knitting a cosy sweater.

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Nagesh Shanbhag

Nagesh Shanbhag, MD-PhD. A native of India, Nagesh completed his basic medical training in Goa, India before embarking on an international career. He has a MSc in Experimental & Clinical Neurosciences from University of Regensburg, Germany and a PhD in neurosciences from University of Groningen, The Netherlands. Nagesh also has postdoctoral experience from Uniformed Services University, part of the US federal government and is now developing new methods to study glymphatic function and manipulations of the system for translational relevance. Besides research in the lab, Nagesh is also an avid painter who made the cover of World Neurosurgery journal (Vol. 116, 2018). Nagesh is also the lab’s prankster, and when he has a spare moment he likes to set up pranks or give the PI heart attacks by saying that grants have not been submitted when in fact they have.

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Marios Kritsilis

Marios Kritsilis, MD. Marios is a medical doctor from Athens, Greece. His passion for neurosciences brought him to the North to study the complex physiological mechanisms underlying the glymphatic system. He enjoys hiking and watching Swedish cinema, although he secretly misses the warm greek weather.

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Sam Madjidian

Sam Madjidian, M.Sc. Sam is the only full time Swedish-born lab member and handles all the translations from English to Swedish for the lab. Sam is the research administrator for the group and Iben’s Swedish-conversation partner. Sam also speaks Greek and Farsi (and Portuguese/Spanish) and enjoys working and practicing with his language skills. He shares an office with Nagesh Shanbhag and has recently been recruited to Shanbhag’s School for Gifted Pranksters, an opportunity of a lifetime. His last name Madjidian might actually be Magician misspelled on his birth certificate. No one knows, it is all a mystery!

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Chenchen Liu

Chenchen Liu, MD-PhD. Chenchen is from, China, and moved to Sweden with his family to train in the glymphatic system. Chenchen likes steaks and green tea and playing football with his daughter. Each of the Chen’s in Chenchen’s name mean different things. The first means morning and the last means dragon.

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Max Wictor

Max Wictor, MD student. Max is from Sweden and worked at a pharmacy before starting medical school. Max helps assist with the 7 Tesla MRI and he has just started to discover the world of the glymphatic system. When Max isn’t googling all the new English words and concepts, he likes to play the electric bass in a band or play around with some nice chords on the piano.

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Collaborators

The Lundgaard Lab collaborates with groups locally and internationally. We collaborate with a network of WCMM-groups and the SciLife Labs.

 

Angela Cenci-Nilsson (Parkinson’s disease), Lund University

Tomas Deierborg (microglia and neuroinflammation), Lund University

Anja Meissner (cardiovascular system), WCMM, Lund University

Maiken Nedergaard (glymphatic system and astrocytes), Copenhagen University and University of Rochester

Daniel Globisch (metabolomics), Uppsala University and SciLife Lab

Andrew West (Parkinson’s disease), Duke University

Job vacancies

The Lundgaard Lab does not have any position open currently, however we are always interested to hear from prospective students and postdocs.

Please contact: iben.lundgaard@med.lu.se.

Bibliography

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

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. (2018) Aquaporin-4 dependent glymphatic solute transport in rodent brain. eLife 2018;7:e40070

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

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.

Bèchet NB, Kylkilahti TM, Mattsson B, Petrasova M, Shanbhag NC, Lundgaard I. (2020) Light sheet fluorescence microscopy of optically cleared brains for studying the glymphatic system. Journal of Cerebral Blood Flow and Metabolism 40(10):1975-1986

Fisher J, Pavan C, Ohlmeier LS, Nilson B, Lundgaard I, Linder A, Bentzer P. (2020) A functional observational battery for evaluation of neurological outcomes in a rat model of acute bacterial meningitis. Intensive Care Med Exp 8(1):40

Kylkilahti TM, Berends E, Ramos M, Shanbhag NC, Töger J, Markenroth Bloch K, Lundgaard I. (In press) Achieving brain clearance and preventing neurodegenerative diseases – A glymphatic perspective. Journal of Cerebral Blood Flow and Metabolism

Acknowledgements

The Lundgaard Lab is grateful for the support from the following foundations:


The Knut & Alice Wallenberg Foundation, Vetenskapsrådet (Swedish Research Council), Hjärnfonden (Brain Foundation), The Crafoord Foundation, The Wenner-Gren Foundations, The Åhlén Foundation, Torsten Söderbergs Foundation, Tore Nilsons Foundation.

Contact

Sölvegatan 17, 223 62 Lund, Sweden
Room #: BMC A1304a

+46 (0)46 222 06 21

iben.lundgaard@med.lu.se