ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes
The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arte...
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doaj-ed67bcbde92446528330e60790caff6f2020-11-25T03:04:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-01214371437110.3390/ijms21124371ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 AstrocytesAbby Keable0Ronan O’Neill1Matthew MacGregor Sharp2Maureen Gatherer3Ho Ming Yuen4David Annandale Johnston5Roy Oliver Weller6Roxana Octavia Carare7Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKFaculty of Medicine, University of Southampton, Southampton SO16 6YD, UKThe accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage—IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy.https://www.mdpi.com/1422-0067/21/12/4371apolipoprotein E4 astrocytesbasement membranescorrelative light and electron microscopymillifluidics |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Abby Keable Ronan O’Neill Matthew MacGregor Sharp Maureen Gatherer Ho Ming Yuen David Annandale Johnston Roy Oliver Weller Roxana Octavia Carare |
spellingShingle |
Abby Keable Ronan O’Neill Matthew MacGregor Sharp Maureen Gatherer Ho Ming Yuen David Annandale Johnston Roy Oliver Weller Roxana Octavia Carare ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes International Journal of Molecular Sciences apolipoprotein E4 astrocytes basement membranes correlative light and electron microscopy millifluidics |
author_facet |
Abby Keable Ronan O’Neill Matthew MacGregor Sharp Maureen Gatherer Ho Ming Yuen David Annandale Johnston Roy Oliver Weller Roxana Octavia Carare |
author_sort |
Abby Keable |
title |
ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes |
title_short |
ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes |
title_full |
ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes |
title_fullStr |
ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes |
title_full_unstemmed |
ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes |
title_sort |
apoe4 astrocytes secrete basement membranes rich in fibronectin and poor in laminin compared to apoe3 astrocytes |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-06-01 |
description |
The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage—IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy. |
topic |
apolipoprotein E4 astrocytes basement membranes correlative light and electron microscopy millifluidics |
url |
https://www.mdpi.com/1422-0067/21/12/4371 |
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