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Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways
Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways
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. 2μL of 100μM 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 mins later. At 5 mins, 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 mins, 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.
0001-6322
1-38
Albargothy, Nazira J.
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Johnston, David A.
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MacGregor-Sharp, Matthew
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Weller, Roy O.
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Verma, Ajay
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Hawkes, Cheryl A.
031a17ac-0931-4ff9-93cc-df8cb58e14f7
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa
Albargothy, Nazira J.
ec692e7e-550c-4914-a7c6-c8eb934b1a0f
Johnston, David A.
b41163c9-b9d2-425c-af99-2a357204014e
MacGregor-Sharp, Matthew
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Weller, Roy O.
4a501831-e38a-4d39-a125-d7141d6c667b
Verma, Ajay
5a207350-0de9-487a-be28-f9eb2f558140
Hawkes, Cheryl A.
031a17ac-0931-4ff9-93cc-df8cb58e14f7
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa

Albargothy, Nazira J., Johnston, David A., MacGregor-Sharp, Matthew, Weller, Roy O., Verma, Ajay, Hawkes, Cheryl A. and Carare, Roxana O. (2018) Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathologica, 1-38. (doi:10.1007/s00401-018-1862-7).

Record type: Article

Abstract

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. 2μL of 100μM 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 mins later. At 5 mins, 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 mins, 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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Accepted/In Press date: 5 May 2018
e-pub ahead of print date: 12 May 2018

Identifiers

Local EPrints ID: 420950
URI: https://eprints.soton.ac.uk/id/eprint/420950
ISSN: 0001-6322
PURE UUID: 1333346c-cc1f-48e0-bb39-9eb2140f4ed7
ORCID for Nazira J. Albargothy: ORCID iD orcid.org/0000-0003-1435-8612
ORCID for David A. Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Matthew MacGregor-Sharp: ORCID iD orcid.org/0000-0002-6623-5078

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Date deposited: 18 May 2018 16:30
Last modified: 14 Mar 2019 01:40

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