title: Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.
abstract: Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Peng
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Thiyagarajan M
authors.initials: TM
authors.lastname: Achariyar
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Humberto
authors.initials: H
authors.lastname: Mestre
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Hitomi
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Regan
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Tristan
authors.initials: T
authors.lastname: Kasper
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Peng
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Anesthesia, Stony Brook University, Stony Brook, NY, USA; Department of Radiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Benveniste
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
authors.affiliation: Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: Rashid_Deane@urmc.rochester.edu.
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides
keywords: AQP4; Alzheimer's disease; Amyloid-β; Astrocytes; Brain ISF clearance; CSF; Clearance; Convective ISF flow; Glymphatic pathways; Lymphatic system