title: Vascular basement membranes as pathways for the passage of fluid into and out of the brain.
abstract: In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aβ, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aβ was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.
authors.forename: Alan W J
authors.initials: AW
authors.lastname: Morris
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.
authors.forename: Matthew MacGregor
authors.initials: MM
authors.lastname: Sharp
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.
authors.forename: Nazira J
authors.initials: NJ
authors.lastname: Albargothy
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.
authors.forename: Rute
authors.initials: R
authors.lastname: Fernandes
authors.affiliation: Open University, Milton Keynes, Buckinghamshire, MK7 6AA, UK.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hawkes
authors.affiliation: Biogen, Binney Street, Cambridge, MA, 02142, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Verma
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.
authors.forename: Roy O
authors.initials: RO
authors.lastname: Weller
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK. rcn@soton.ac.uk.
authors.forename: Roxana O
authors.initials: RO
authors.lastname: Carare
mesh_terms: D000199:Actins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D019921:Biotinylation; D001808:Blood Vessels / Q000166:cytology*; D002555:Cerebrospinal Fluid / Q000187:drug effects / Q000378:metabolism; D002946:Cisterna Magna / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007797:Laminin / Q000378:metabolism; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000199:Actins; D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D007797:Laminin; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Amyloid-β; Arteries; Basement membranes; Capillaries; Drug delivery; Lymphatic drainage; Nanoparticles neuroimmunology; Virchow–Robin space