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Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways
Open accessAbstract
Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the "glymphatic system" that proposes tracers enter the brain along periarterial "spaces" and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular "spaces" around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 μL of 100 μM soluble, fluorescent fixable amyloid β (Aβ) were injected into the CSF of the cisterna magna of 6-10 and 24-30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed Aβ on the outer aspects of cortical arteries colocalized with α-2 laminin in the pial-glial basement membranes. At 30 min, Aβ was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer's disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA.
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“Intriguingly, multiple orthogonal studies suggest that the striatum receives the most perivascular CSF flow, highlighting the potential of this transport pathway for accessing deep brain structures.15,16”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [16]
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Metadata
- Authors
- Albargothy, N. J., Johnston, D. A., MacGregor-Sharp, M., Weller, R. O., Verma, A., Hawkes, C. A., & Carare, R. O.
- Affiliations
- University of Southampton (GB)
- Biogen (United States) (US)
- The Open University (GB)
- Corresponding author
- Carare, Roxana O.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2018-05-12
- Volume
- 136
- Issue
- 1
- Pages
- 139-152
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6015107
- OpenAlex
- W2801110912
- Cited by
- 311
- References
- 40
- Citations by year
- 2026: 23 · 2025: 40 · 2024: 35 · 2023: 36 · 2022: 46 · 2021: 41 · 2020: 47 · 2019: 32 · 2018: 10
- FWCI
- 14.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Research Online - ORO (The Open University) (acceptedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Funders
- Biogen (FE-13227)
- Topics
- Health Sciences › Medicine › Clinical Neurology › 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
- glymphatic system, cerebrospinal fluid, amyloid-beta, cortical arteries, laminin alpha 2, type IV collagen, cerebral amyloid angiopathy, Alzheimer's disease, interstitial fluid drainage
- MeSH terms
- Parenchymal Tissue, Glymphatic System, CD163 Antigen, Actins, Age Factors, Animals, Basement Membrane, Blood Vessels, Brain, Cerebrospinal Fluid, Glial Fibrillary Acidic Protein, Male, Mice, Inbred C57BL, Receptors, Cell Surface, Time Factors, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Amyloid beta-Peptides, Fluorescein-5-isothiocyanate, Collagen Type IV, Extracellular Fluid, Mice
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