title: Enhanced interstitial fluid drainage in the hippocampus of spontaneously hypertensive rats.
abstract: Hypertension is associated with cognitive decline and various forms of dementia, including Alzheimer's disease. In animal models of hypertension, many of Alzheimer's disease characteristics are recapitulated, including brain atrophy, cognitive decline, amyloid β accumulation and blood brain barrier dysfunction. Removal of amyloid β and other waste products depends in part on clearance via the brain interstitial fluid (ISF). Here we studied the impact of hypertension on ISF drainage, using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). At 8 months, high (500 kD) and low (3 kD) fluorescent molecular weight tracers released passively into the hippocampus showed a drastically enhanced spreading in SHR. Tracer spreading was inhomogeneous, with accumulation at ISF-CSF borders, around arteries, and towards the stratum lacunosum moleculare. These locations stained positively for the astrocyte marker GFAP, and aquaporin 4. Despite enhanced dispersion, clearance of tracers was not affected in SHR. In conclusion, these data indicate enhanced bulk flow of ISF in the hippocampus of hypertensive rats. ISF drains along astrocytes towards the cerebrospinal fluid compartment, which leads to sieving of high molecular weight solutes. Sieving may lead to a local increase in the concentration of waste products and potentially promotes the aggregation of amyloid β.
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bedussi
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Daphne M P
authors.initials: DMP
authors.lastname: Naessens
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: de Vos
authors.affiliation: Division of Nephrology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: Olde Engberink
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU medical center, Amsterdam, The Netherlands.
authors.forename: Micha M M
authors.initials: MMM
authors.lastname: Wilhelmus
authors.affiliation: Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands.|Department of Neurology, Radboud University Medical Centre, Nijmegen, Netherlands.
authors.forename: Edo
authors.initials: E
authors.lastname: Richard
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Malyssa
authors.initials: M
authors.lastname: Ten Hove
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ed
authors.identifier: http://orcid.org/0000-0001-8654-986X
authors.initials: E
authors.lastname: vanBavel
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands. n.t.bakker@amc.uva.nl.
authors.forename: Erik N T P
authors.initials: ENTP
authors.lastname: Bakker
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004322:Drainage; D045604:Extracellular Fluid / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007477:Ions / Q000378:metabolism; D008856:Microscopy, Fluorescence; D061848:Optical Imaging; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D051401:Aquaporin 4; D015415:Biomarkers; D005456:Fluorescent Dyes; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D007477:Ions