Roles of aquaporin-4 in brain fluid dynamics
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AbstractWater transport into and out of the brain is essential for life. Abnormal water transport is a hallmark of many neurological disorders and may be fatal. This thesis adds new insights into brain water transport on both a macroscopic and a molecular level. Macroscopically, movement of water between major brain fluid compartments are studied to better understand fluid circulation patterns. On the molecular level, the distribution and roles of the predominant brain water channel aquaporin-4 (AQP4), is being investigated. AQP4 water channels are abundant in glial cell membranes at the brain-blood and brain-cerebrospinal fluid interfaces and are potential therapeutic targets when treating conditions like stroke, brain trauma and Alzheimer's disease. By use of imaging techniques such as electron microscopy, immunofluorescence and in vivo two-photon laser scanning microscopy, we conclude with novel precision that the distribution pattern of AQP4 varies between different brain areas, between brain cell types, and between areas within the individual brain cell. We also discover an hitherto unknown paravascular cerebrospinal fluid circulation pathway that seems to be important for clearance of water and brain waste products. One of the substances being cleared by this system is amyloid-beta, which is known to accumulate in Alzheimer's disease. The discovery of the novel fluid circulation pathway have numerous implications and may pave the way for new treatment strategies of many neurological disorders.
List of papers
Papers I, III and IV are removed due to publisher restrictions.
Paper I: Molecular scaffolds underpinning macroglial polarization: an analysis of retinal Müller cells and brain astrocytes in mouse. Rune Enger, Georg Andreas Gundersen, Nadia Nabil Haj-Yasein, Martine Eilert-Olsen, Anna Elisabeth Thoren, Gry Fluge Vindedal, Finn-Mogens S. Haug, Petur Henry Petersen, Maiken Nedergaard and Erlend A. Nagelhus. Glia. 2012 Dec;60(12):2018-26. Epub 2012 Sep 17. doi: 10.1002/glia.22416
Paper II: Evidence that pericytes regulate aquaporin-4 polarization in mouse cortical astrocytes. Georg Andreas Gundersen, Gry Fluge Vindedal, Øivind Skare, Erlend A. Nagelhus. Submitted manuscript. 2013. Published in Brain Structure and Function (August 2013). doi: 10.1007/s00429-013-0629-0
Paper III: Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Nadia Nabil Haj-Yasein, Gry Fluge Vindedal, Martine Eilert-Olsen, Georg Andreas Gundersen, Øivind Skare, Petter Laake, Arne Klungland, Anna E. Thoren, John M. Burkhardt, Ole Petter Ottersen and Erlend A. Nagelhus. Proceedings of the National Academy of Sciences U S A. 2011 Oct 25;108(43):17815-20. Epub 2011 Oct 11. doi: 10.1073/pnas.1110655108
Paper IV: A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid ß. Jeffrey J. Iliff, Minghuan Wang, Yonghong Liao, Benjamin A. Plogg, Weiguo Peng, Georg Andreas Gundersen, Helene Benveniste, G. Edward Vates, Rashid Deane, Steven A. Goldman, Erlend A. Nagelhus, Maiken Nedergaard. Science Translational Medicine. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748