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GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis Kajiwara, Yuji; Wang, Erming; Wang, Minghui; Sin, Wun C; Brennand, Kristen J.; Schadt, Eric; Naus, Christian C; Buxbaum, Joseph; Zhang, Bin

Abstract

GJA1 (connexin43) has been predicted as the top key driver of an astrocyte enriched subnetwork associated with Alzheimer’s disease (AD). In this study, we comprehensively examined GJA1 expression across 29 transcriptomic and proteomic datasets from post-mortem AD and normal control brains. We demonstrated that GJA1 was strongly associated with AD amyloid and tau pathologies and cognitive functions. RNA sequencing analysis of Gja1−/− astrocytes validated that Gja1 regulated the subnetwork identified in AD, and many genes involved in Aβ metabolism. Astrocytes lacking Gja1 showed reduced Apoe protein levels as well as impaired Aβ phagocytosis. Consistent with this, wildtype neurons co-cultured with Gja1−/− astrocytes contained higher levels of Aβ species than those with wildtype astrocytes. Moreover, Gja1−/− astrocytes was more neuroprotective under Aβ stress. Our results underscore the importance of GJA1 in AD pathogenesis and its potential for further investigation as a promising pharmacological target in AD.

Item Metadata

Title
GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis
Creator
Kajiwara, Yuji; Wang, Erming; Wang, Minghui; Sin, Wun C; Brennand, Kristen J.; Schadt, Eric; Naus, Christian C; Buxbaum, Joseph; Zhang, Bin
Publisher
BioMed Central
Date Issued
2018-12-21
Description
GJA1 (connexin43) has been predicted as the top key driver of an astrocyte enriched subnetwork associated with Alzheimer’s disease (AD). In this study, we comprehensively examined GJA1 expression across 29 transcriptomic and proteomic datasets from post-mortem AD and normal control brains. We demonstrated that GJA1 was strongly associated with AD amyloid and tau pathologies and cognitive functions. RNA sequencing analysis of Gja1−/− astrocytes validated that Gja1 regulated the subnetwork identified in AD, and many genes involved in Aβ metabolism. Astrocytes lacking Gja1 showed reduced Apoe protein levels as well as impaired Aβ phagocytosis. Consistent with this, wildtype neurons co-cultured with Gja1−/− astrocytes contained higher levels of Aβ species than those with wildtype astrocytes. Moreover, Gja1−/− astrocytes was more neuroprotective under Aβ stress. Our results underscore the importance of GJA1 in AD pathogenesis and its potential for further investigation as a promising pharmacological target in AD.
Subject
Alzheimer’s disease; GJA1; Cx43; connexin43; Gene networks; amyloidβ; Astrocyte
Genre
Article
Type
Text
Language
eng
Date Available
2018-12-21
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0375819
URI
http://hdl.handle.net/2429/68129
Affiliation
Medicine, Faculty of; Non UBC; Cellular and Physiological Sciences, Department of
Citation
Acta Neuropathologica Communications. 2018 Dec 21;6(1):144
Publisher DOI
10.1186/s40478-018-0642-x
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s).
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)