Description of the research breakthrough
Maike Nedergaard has emerged as a researcher of outstanding merit due to her groundbreaking elucidation of the glymphatic system, a discovery that has pivoted the scientific community towards a novel understanding of brain health, particularly in the realm of sleep and its protective roles against neurodegenerative disorders. By highlighting the glymphatic system’s role in eliminating potential neurotoxic metabolites including β-amyloid during sleep, Dr. Nedergaard has forged new pathways in sleep research, providing crucial insights between sleep and neurodegenerative diseases.
Her scholarship has pierced through the conventional paradigms of neurobiology, uncovering the pivotal role that sleep plays in cognitive preservation and exploring the multifaceted relationships between sleep, the glymphatic system, and neurodegenerative diseases. Nedergaard’s research has provided the critical lens through which we perceive sleep’s influence on cognitive health, providing a robust framework that guides current and future explorations into these interconnected domains.
Nedergaard’s pioneering work has catalyzed the ongoing development of promising new strategies for diagnosing and treating a variety of brain disorders, will have lasting implications for the field of neuroscience, and may lead to new diagnostic tools and treatments for neurodegenerative diseases. In a world where the fastest growing segment of our population is people over the age of 65, Dr. Nedergaard has provided transformative insights and ushered in a new era of therapeutic exploration through sleep.
Background to the research
Maike Nedergaard’s work has deeply enriched our understanding of the brain’s capacity for self-regulation and maintenance. Her research embodies the spirit of scientific excellence that has resulted in discovery and advanced the frontiers of biological knowledge, as celebrated by the Nakasone Award.
Prior to 2012, the scientific community did not fully comprehend how waste is removed from the brain, namely because the lymphatic system, which is responsible for disposing cellular waste in the rest of the body, was not mapped to the central nervous system. This gap in knowledge of a fundamental process of biology limited our understanding of neurodegenerative disorders which are characterized by protein accumulations in the brain.
Over the past decade, Nedergaard's innovative research has introduced the glymphatic system as a pivotal mechanism responsible for detoxifying and maintaining the brain's health, while illustrating its profound connections with sleep and various neurodegenerative diseases. Facilitated by Aquaporin-4, the glymphatic system plays a crucial role in clearing β-amyloid during sleep, thereby shedding light on the intricate relationship between sleep and cerebral health and transforming our understanding of brain physiology and neurodegenerative disorders. One of the most intriguing aspects of the glymphatic system is that it is primarily active during sleep and shuts down shortly after awakening. This observation may explain the century-old question of why we need to sleep: we sleep because we need to clear the brain of metabolic waste products that accumulate during wakefulness. The loss of a normal sleep architecture accelerates the progression of neurodegenerative diseases by insufficient clearance of Amyloid-b, Tau, a-synuclein, huntingtin (Htt) and TDP-43 peptide/proteins. This concept has received considerable attention because dementing diseases, such as Alzheimer’s, Parkinson’s, and Huntington diseases, as well as frontotemporal dementia, are often preceded by years of sleep disturbances.
The exploration into the increased activity of the glymphatic system during sleep has shed new light on the relationship between sleep disturbances and brain diseases, sparking fresh avenues of research and potential interventions. The sheer number of studies alone that followed Dr. Nedergaard’s discovery demonstrates the importance of glymphatic clearance in essentially all neurological diseases studied to date. Subsequent research from Nedergaard’s own lab and others have shown that circadian rhythms and certain patterns of neurological activity play a role in controlling the glymphatic system, and that the meningeal membranes organize flow in the cerebrospinal fluid filled spaces around the brain. Studies from Nedergaard’s lab have also shown that the glymphatic system deteriorates while we age and can be impaired by disrupted sleep, hypertension, and traumatic brain injury. The glymphatic system can be used for delivery of drugs that are impermeable to the blood brain barrier and has a great potential as a novel approach to drug delivery to the central nervous system, one of the biggest challenges in treating neurodegenerative disorders. Finally, her work has also shown that the initial brain edema that develops after stroke and cardiac arrest results from an influx of cerebrospinal fluid and not from an inflow of vascular fluid as described in the textbooks.
Maiken Nedergaard has transformed our understanding of the importance of sleep through her groundbreaking discovery and exploration of the glymphatic system. Her work transcends a mere discovery, establishing a robust framework that influences not only sleep medicine but also interweaves with advancements in neuroscience and neuroimmunology, casting a wide interdisciplinary impact across several scientific arenas. In this regard, Nedergaard’s work is more than a singular discovery; it is a cornerstone in a transformative narrative unfolding in the fields of neuroscience, neuroimmunology, sleep medicine, and drug delivery. Several innovations in the neuroimaging field now allow for identification of patients with suppressed glymphatic clearance; its use as a biomarker of glymphatic insufficiency is ideally suited to track the efficacy of novel therapeutic approaches.
Standing
Dr. Nedergaard is an elected member of the Academia Europaea, the Royal Danish Academy of Sciences and Letters, and the Royal Academy of Pharmacy of Spain. She has received a number of awards in recognition of her research, including one of Science Magazine’s top ten “Breakthroughs of the Year,” the Newcomb Cleveland Prize from the American Association for the Advancement of Science (AAAS), the Alzheimer Prize from the Danish Alzheimer Association, the Nordic Fernström Prize, the International Prize of Translational Neuroscience, the Outstanding Scientific Achievement Award from the Sleep Research Society, and the Anders Jahre’s Award for Medical Research.
She has published more than 430 Medline indexed articles and 21 book chapters, and she is the most highly cited researcher at the University of Rochester. She has presented her work at over 240 invited talks, and has mentored hundreds of students and post-docs, many of whom have pursued their own careers in sleep research.
Biography/CV: Nedergaard attended the University of Copenhagen, where she received an M.D. in 1983 and a D.M.Sc in 1988. She completed post-doctoral training in neuropathology/physiology at the University of Copenhagen (1984-1987) and subsequently in neuroscience at Weill Cornell Medicine (1987-1988). Dr. Nedergaard is currently the co-director for the Center for Translational Neuromedicine, oversees the Division of Glial Disease and Therapeutics within the Center, and is a Professor of Neuroscience, Neurosurgery, and Neurology at the University of Rochester. In addition, she is also the co-director of the Center for Translational Neuromedicine and Professor of Glial Cell Biology at the University of Copenhagen.
Her interests range from neuron-glia interactions to the role of astrocytes in aging, small vessel disease, stroke and cerebral blood flow. Her group described the glymphatic system, a brain equivalent of the lymphatic system, within which cerebrospinal fluid diffuses rapidly and mixes with interstitial fluids, thereby filtering metabolic byproducts that accumulate due to neuronal activity. The glymphatic system dramatically increases its activity during sleep; brain cleaning and detoxification are thus facilitated during sleep, providing a novel and direct explanation for sleep’s restorative effect.
Dr. Nedergaard is an elected member of the Academia Europaea, the Royal Danish Academy of Sciences and Letters, and the Royal Academy of Pharmacy of Spain. She has received a number of awards in recognition of her research, including one of Science Magazine’s top ten “Breakthroughs of the Year,” the Newcomb Cleveland Prize from the American Association for the Advancement of Science (AAAS), the Alzheimer Prize from the Danish Alzheimer Association, the Nordic Fernström Prize, the International Prize of Translational Neuroscience, the Outstanding Scientific Achievement Award from the Sleep Research Society, and the Anders Jahre’s Award for Medical Research. She has published more than 430 Medline indexed articles and 21 book chapters, and she is the most highly cited researcher at the University of Rochester. She has presented her work at over 240 invited talks, and has mentored hundreds of students and post-docs, many of whom have pursued their own research careers.
Publications:
Xie, L., Kang, H., Xu, Q., Chen, M.J., Liao, Y., Thiyagarajan, M., O'Donnell, J., Christensen, D.J., Nicholson, C., Iliff, J.J., et al. (2013). Sleep drives metabolite clearance from the adult brain. Science 342, 373-377. 10.1126/science.1241224.
Hablitz LM, Plá V, Giannetto M, Vinitsky HS, Stæger FF, Metcalfe T, Nguyen R, Benrais A, Nedergaard M. (2020) Circadian control of brain glymphatic and lymphatic fluid flow. Nature communications. 11(1):4411
Mestre H, Du T, Sweeney AM, Liu G, Samson AJ, Peng W, Mortensen KN, Stæger FF, Bork PAR, Bashford L, Toro ER, Tithof J, Kelley DH, Thomas JH, Hjorth PG, Martens EA, Mehta RL, Solis O, Blinder P, Kleinfeld D, Hirase H, Mori Y, Nedergaard M. (2020) Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science 367(6483):eaax7171.
Nedergaard, M., and Goldman, S.A. (2020). Glymphatic failure as a final common pathway to dementia. Science 370, 50-56. 10.1126/science.abb8739.
Møllgård K, Beinlich FRM, Kusk P, Miyakoshi LM, Delle C, Plá V, Hauglund NL, Esmail T, Rasmussen MK, Gomolka RS, Mori Y, Nedergaard M. (2023) A mesothelium divides the subarachnoid space into functional compartments. Science. 2023 Jan 6; 379(6627):84-88.