The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

ApoE4 astrocytes secrete basement membranes rich in fibronectin and poor in laminin compared to ApoE3 astrocytes

ApoE4 astrocytes secrete basement membranes rich in fibronectin and poor in laminin compared to ApoE3 astrocytes
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 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.

Apolipoprotein E4 astrocytes, Basement membranes, Correlative light and electron microscopy, Millifluidics
1422-0067
1-13
Keable, Abby
175d97e8-3baf-4130-94a8-f981810e2c96
O'Neill, Ronan
639dce71-1b32-473f-ba04-17d8c4d42067
MacGregor Sharp, Matthew
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Gatherer, Maureen
b0aae216-21c4-4737-b042-865a65658f06
Yuen, Ho Ming
b1df4c57-0c2a-44ac-ab40-22b88e8effe8
Johnston, David Annandale
b41163c9-b9d2-425c-af99-2a357204014e
Weller, Roy Oliver
4a501831-e38a-4d39-a125-d7141d6c667b
Carare, Roxana Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Keable, Abby
175d97e8-3baf-4130-94a8-f981810e2c96
O'Neill, Ronan
639dce71-1b32-473f-ba04-17d8c4d42067
MacGregor Sharp, Matthew
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Gatherer, Maureen
b0aae216-21c4-4737-b042-865a65658f06
Yuen, Ho Ming
b1df4c57-0c2a-44ac-ab40-22b88e8effe8
Johnston, David Annandale
b41163c9-b9d2-425c-af99-2a357204014e
Weller, Roy Oliver
4a501831-e38a-4d39-a125-d7141d6c667b
Carare, Roxana Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa

Keable, Abby, O'Neill, Ronan, MacGregor Sharp, Matthew, Gatherer, Maureen, Yuen, Ho Ming, Johnston, David Annandale, Weller, Roy Oliver and Carare, Roxana Octavia (2020) ApoE4 astrocytes secrete basement membranes rich in fibronectin and poor in laminin compared to ApoE3 astrocytes. International Journal of Molecular Sciences, 21 (12), 1-13, [4371]. (doi:10.3390/ijms21124371).

Record type: Article

Abstract

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.

Text
ijms-21-04371 - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)

More information

Accepted/In Press date: 16 June 2020
e-pub ahead of print date: 19 June 2020
Published date: June 2020
Keywords: Apolipoprotein E4 astrocytes, Basement membranes, Correlative light and electron microscopy, Millifluidics

Identifiers

Local EPrints ID: 442776
URI: http://eprints.soton.ac.uk/id/eprint/442776
ISSN: 1422-0067
PURE UUID: c39a4313-cb7f-4dcf-a0f6-3e0d5f297488
ORCID for Matthew MacGregor Sharp: ORCID iD orcid.org/0000-0002-6623-5078
ORCID for David Annandale Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Roxana Octavia Carare: ORCID iD orcid.org/0000-0001-6458-3776

Catalogue record

Date deposited: 27 Jul 2020 16:30
Last modified: 09 Jan 2022 03:33

Export record

Altmetrics

Contributors

Author: Abby Keable
Author: Ronan O'Neill
Author: Matthew MacGregor Sharp ORCID iD
Author: Maureen Gatherer
Author: Ho Ming Yuen
Author: David Annandale Johnston ORCID iD
Author: Roy Oliver Weller

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×