Vascular basement membranes as pathways for the passage of fluid into and out of the brain
Open accessAbstract
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.
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Animal studies report diverging findings regarding the sites of perivascular brain influx and efflux and direction of perivascular flow.
“Moreover, animal studies report diverging findings regarding the sites of perivascular brain influx and efflux and direction of perivascular flow (7, 15, 16).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [16]
The Discussion (Fig. 6; page not provided) and Conclusions describe different perivascular routes for CSF influx and interstitial-fluid efflux, with flow in opposite directions. They do not say that animal studies report conflicting findings about those routes or flow directions; the paper presents the routes as distinct and notes an unresolved question about transport within capillary basement membranes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn the cortex, a packed barrier of endothelial cells, basement membrane, and glia limitans surrounds penetrating arteries, leaving little to no fluid-filled space, whereas the lenticulostriate branches in the basal ganglia are surrounded by a larger perivascular space.
“For example, in the cortex, a packed barrier of endothelial cells, basement membrane, and glia limitans surrounds penetrating arteries, leaving little to no fluid-filled space, whereas the lenticulostriate branches in the basal ganglia are surrounded by a larger perivascular space (13).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [13]
Movement of ISF from the brain parenchyma occurs primarily between basement membranes in the perivascular spaces of capillaries and arteries, continuing along basement membranes in the tunica media of cerebral and leptomeningeal arteries.
“Movement of ISF from the brain parenchyma occurs primarily between basement membranes in the perivascular spaces of capillaries and arteries. This continues along basement membranes in the tunica media of cerebral and leptomeningeal arteries (13).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [13]
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- Authors
- Morris, A. W. J., Sharp, M. M., Albargothy, N. J., Fernandes, R., Hawkes, C. A., Verma, A., Weller, R. O., & Carare, R. O.
- Affiliations
- Southampton General Hospital (GB)
- The Open University (GB)
- Biogen (United States) (US)
- Corresponding author
- Carare, Roxana O.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2016-03-14
- Volume
- 131
- Issue
- 5
- Pages
- 725-736
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4835509
- OpenAlex
- W2298591538
- Cited by
- 289
- References
- 29
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 18 · 2023: 22 · 2022: 35 · 2021: 28 · 2020: 48 · 2019: 33 · 2018: 29 · 2017: 34 · 2016: 9
- FWCI
- 19.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Research Online - ORO (The Open University) (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/K015540/1)
- Age UK (PhD-368)
- Biogen Idec
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- vascular basement membrane, cerebrospinal fluid, glymphatic system, interstitial fluid drainage, amyloid-beta, gold nanoparticles, glia limitans, cerebral microvasculature, perivascular spaces, brain drug delivery, neuroimmunology, Alzheimer's disease, hippocampus
- MeSH terms
- Actins, Animals, Basement Membrane, Blood Vessels, Cerebrospinal Fluid, Cisterna Magna, Extracellular Space, Fluorescent Dyes, Hippocampus, Laminin, Male, Mice, Inbred C57BL, Peptide Fragments, Amyloid beta-Peptides, Biotinylation, Microscopy, Electron, Transmission, Mice, Metal Nanoparticles
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