Combined effects of aquaporin-4 and hypoxia produce age-related hydrocephalus |
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Authors: | José Luis Trillo-Contreras Reposo Ramírez-Lorca Laura Hiraldo-González Ismael Sánchez-Gomar Ana Galán-Cobo Nela Suárez-Luna Eva Sánchez de Rojas-de Pedro Juan José Toledo-Aral Javier Villadiego Miriam Echevarría |
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Institution: | 1. Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital. (HUVR)/Spanish National Research Council (CSIC)/University of Seville, Seville 41013, Spain;2. Department of Physiology and Biophysics, University of Seville, Seville 41009, Spain;3. Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Spain |
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Abstract: | Aquaporin-4, present in ependymal cells, in glia limiting and abundantly in pericapillary astrocyte foot processes, and aquaporin-1, expressed in choroid plexus epithelial cells, play an important role in cerebrospinal fluid production and may be involved in the pathophysiology of age-dependent hydrocephalus. The finding that brain aquaporins expression is regulated by low oxygen tension led us to investigate how hypoxia and elevated levels of cerebral aquaporins may result in an increase in cerebrospinal fluid production that could be associated with a hydrocephalic condition. Here we have explored, in young and aged mice exposed to hypoxia, whether aquaporin-4 and aquaporin-1 participate in the development of age-related hydrocephalus. Choroid plexus, striatum, cortex and ependymal tissue were analyzed separately both for mRNA and protein levels of aquaporins. Furthermore, parameters such as total ventricular volume, intraventricular pressure, cerebrospinal fluid outflow rate, ventricular compliance and cognitive function were studied in wild type, aquaporin-1 and aquaporin-4 knock-out animals subjected to hypoxia or normoxia. Our data demonstrate that hypoxia is involved in the development of age-related hydrocephalus by a process that depends on aquaporin-4 channels as a main route for cerebrospinal fluid movement. Significant increases in aquaporin-4 expression that occur over the course of animal aging, together with a reduced cerebrospinal fluid outflow rate and ventricular compliance, contribute to produce more severe hydrocephalus related to hypoxic events in aged mice, with a notable impairment in cognitive function. These results indicate that physiological events and/or pathological conditions presenting with cerebral hypoxia/ischemia contribute to the development of chronic adult hydrocephalus. |
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Keywords: | AQP4 Hypoxia Aging Mice Hydrocephalus Cerebrospinal fluid |
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