Roles of aquaporin-4 in brain fluid dynamics

Abstract

Water 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.