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Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO - Acta Neuropathol. (2016)

Bottom Line: Nanoparticles did not enter capillary basement membranes from the extracellular spaces.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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the lymphatic drainage and convective influx/glymphatic systems of the brain. An artery enters the brain from the subarachnoid space and an arteriole divides into capillaries. At the top of the figure, the artery is lined by endothelium (Endo), and coated by the tunica media (TM) composed of smooth muscle cells and by the outermost tunica adventitia (TA) composed of connective tissue. As it enters the brain, the artery loses the tunica adventitia but is still coated by a layer of pia-arachnoid (Pia) that intervenes between the artery and the glia limitans (GL) of the brain. As the arteriole divides into capillaries, the tunica media and the layer of pia mater are lost. Thus, at the level of the capillary, the glia limitans is in direct contact with the wall of the capillary. On the right-hand side of the diagram, the red arrows indicate the intramural perivascular lymphatic drainage pathway by which interstitial fluid (ISF) and solutes pass out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of arterioles and arteries [7]. Tracers in the CSF enter the brain along the pial-glial basement membrane between the pia mater and the glia limitans (indicated by a green arrow) and enter the brain parenchyma and interstitial fluid by an aquaporin 4-dependent mechanism, which is the convective influx/glymphatic pathway
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Fig6: Schematic representation of the lymphatic drainage and convective influx/glymphatic systems of the brain. An artery enters the brain from the subarachnoid space and an arteriole divides into capillaries. At the top of the figure, the artery is lined by endothelium (Endo), and coated by the tunica media (TM) composed of smooth muscle cells and by the outermost tunica adventitia (TA) composed of connective tissue. As it enters the brain, the artery loses the tunica adventitia but is still coated by a layer of pia-arachnoid (Pia) that intervenes between the artery and the glia limitans (GL) of the brain. As the arteriole divides into capillaries, the tunica media and the layer of pia mater are lost. Thus, at the level of the capillary, the glia limitans is in direct contact with the wall of the capillary. On the right-hand side of the diagram, the red arrows indicate the intramural perivascular lymphatic drainage pathway by which interstitial fluid (ISF) and solutes pass out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of arterioles and arteries [7]. Tracers in the CSF enter the brain along the pial-glial basement membrane between the pia mater and the glia limitans (indicated by a green arrow) and enter the brain parenchyma and interstitial fluid by an aquaporin 4-dependent mechanism, which is the convective influx/glymphatic pathway

Mentions: The findings in this study have been combined with previous observations and summarised in Figs. 6 and 7. ISF and soluble tracers flow out of the brain along basement membranes initially in the walls of capillaries and then along basement membranes surrounding smooth muscle cells in the tunica media of arteries (shown as a continuous red line in Fig. 6). Tracers from the CSF, on the other hand, enter the brain along basement membranes on the outside of arteries between the pia mater covering of the artery and the glia limitans (Fig. 6). Previous studies have shown that when particulate tracers such as Indian ink are injected into the cisterna magna they pass into basal cisterns of the subarachnoid space and spread along narrow channels either side of major cerebral arteries over the lateral surfaces of the hemisphere [17]. From this compartment of the subarachnoid space, nanoparticles appear to pass through the pia mater on the surface of the brain to enter the pial-glial basement membranes on the outer aspects of penetrating arteries as shown in Fig. 6. A recent study demonstrated that soluble tracers penetrated the parenchyma after injection into cisterna magna, with 3 kDa tracers reaching 64 μm cortical depth [4]. The permeability characteristics of the mouse pia mater have not been fully defined and require further investigation in future studies.Fig. 6


Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO - Acta Neuropathol. (2016)

Schematic representation of the lymphatic drainage and convective influx/glymphatic systems of the brain. An artery enters the brain from the subarachnoid space and an arteriole divides into capillaries. At the top of the figure, the artery is lined by endothelium (Endo), and coated by the tunica media (TM) composed of smooth muscle cells and by the outermost tunica adventitia (TA) composed of connective tissue. As it enters the brain, the artery loses the tunica adventitia but is still coated by a layer of pia-arachnoid (Pia) that intervenes between the artery and the glia limitans (GL) of the brain. As the arteriole divides into capillaries, the tunica media and the layer of pia mater are lost. Thus, at the level of the capillary, the glia limitans is in direct contact with the wall of the capillary. On the right-hand side of the diagram, the red arrows indicate the intramural perivascular lymphatic drainage pathway by which interstitial fluid (ISF) and solutes pass out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of arterioles and arteries [7]. Tracers in the CSF enter the brain along the pial-glial basement membrane between the pia mater and the glia limitans (indicated by a green arrow) and enter the brain parenchyma and interstitial fluid by an aquaporin 4-dependent mechanism, which is the convective influx/glymphatic pathway
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Related In: Results  -  Collection

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Fig6: Schematic representation of the lymphatic drainage and convective influx/glymphatic systems of the brain. An artery enters the brain from the subarachnoid space and an arteriole divides into capillaries. At the top of the figure, the artery is lined by endothelium (Endo), and coated by the tunica media (TM) composed of smooth muscle cells and by the outermost tunica adventitia (TA) composed of connective tissue. As it enters the brain, the artery loses the tunica adventitia but is still coated by a layer of pia-arachnoid (Pia) that intervenes between the artery and the glia limitans (GL) of the brain. As the arteriole divides into capillaries, the tunica media and the layer of pia mater are lost. Thus, at the level of the capillary, the glia limitans is in direct contact with the wall of the capillary. On the right-hand side of the diagram, the red arrows indicate the intramural perivascular lymphatic drainage pathway by which interstitial fluid (ISF) and solutes pass out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of arterioles and arteries [7]. Tracers in the CSF enter the brain along the pial-glial basement membrane between the pia mater and the glia limitans (indicated by a green arrow) and enter the brain parenchyma and interstitial fluid by an aquaporin 4-dependent mechanism, which is the convective influx/glymphatic pathway
Mentions: The findings in this study have been combined with previous observations and summarised in Figs. 6 and 7. ISF and soluble tracers flow out of the brain along basement membranes initially in the walls of capillaries and then along basement membranes surrounding smooth muscle cells in the tunica media of arteries (shown as a continuous red line in Fig. 6). Tracers from the CSF, on the other hand, enter the brain along basement membranes on the outside of arteries between the pia mater covering of the artery and the glia limitans (Fig. 6). Previous studies have shown that when particulate tracers such as Indian ink are injected into the cisterna magna they pass into basal cisterns of the subarachnoid space and spread along narrow channels either side of major cerebral arteries over the lateral surfaces of the hemisphere [17]. From this compartment of the subarachnoid space, nanoparticles appear to pass through the pia mater on the surface of the brain to enter the pial-glial basement membranes on the outer aspects of penetrating arteries as shown in Fig. 6. A recent study demonstrated that soluble tracers penetrated the parenchyma after injection into cisterna magna, with 3 kDa tracers reaching 64 μm cortical depth [4]. The permeability characteristics of the mouse pia mater have not been fully defined and require further investigation in future studies.Fig. 6

Bottom Line: Nanoparticles did not enter capillary basement membranes from the extracellular spaces.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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, MP806, Tremona Road, Southampton, Hampshire, SO16 6YD, UK.

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.

No MeSH data available.


Related in: MedlinePlus