GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis
department or school: Medicine, Faculty of
department or school: Non UBC
department or school: Cellular and Physiological Sciences, Department of
data provider: DSpace
identifier citation: Acta Neuropathologica Communications. 2018 Dec 21;6(1):144
rights copyright: The Author(s).
creator: Kajiwara, Yuji
creator: Wang, Erming
creator: Wang, Minghui
creator: Sin, Wun Chey
creator: Brennand, Kristen J.
creator: Schadt, Eric
creator: Naus, Christian C
creator: Buxbaum, Joseph
creator: Zhang, Bin
issued: 2018-12-21T17:07:31Z
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.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/68129
note: RESEARCH Open AccessGJA1 (connexin43) is a key regulator ofAlzheimer’s disease pathogenesisYuji Kajiwara1,7†, Erming Wang2,3†, Minghui Wang2,3, Wun Chey Sin4, Kristen J. Brennand1,2,5,6, Eric Schadt2,3,Christian C. Naus4, Joseph Buxbaum1,3,5,6 and Bin Zhang2,3*AbstractGJA1 (connexin43) has been predicted as the top key driver of an astrocyte enriched subnetwork associated withAlzheimer’s disease (AD). In this study, we comprehensively examined GJA1 expression across 29 transcriptomic andproteomic datasets from post-mortem AD and normal control brains. We demonstrated that GJA1 was stronglyassociated with AD amyloid and tau pathologies and cognitive functions. RNA sequencing analysis of Gja1−/− astrocytesvalidated that Gja1 regulated the subnetwork identified in AD, and many genes involved in Aβ metabolism. Astrocyteslacking Gja1 showed reduced Apoe protein levels as well as impaired Aβ phagocytosis. Consistent with this, wildtypeneurons 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 GJA1in AD pathogenesis and its potential for further investigation as a promising pharmacological target in AD.Keywords: Alzheimer’s disease, GJA1, Cx43, connexin43, Gene networks, amyloidβ, AstrocyteIntroductionAlzheimer’s disease (AD) reflects multifactorial geneticand environmental perturbations that, in turn, causepleiotropic changes in molecular networks linking a hostof biological processes. By employing an integrative net-work biology approach to analyze a large-scale geneticand gene expression dataset in late onset Alzheimer’sdisease (LOAD), we previously conducted an unbiasedidentification and prioritization of gene networks associatedwith clinical and pathological progression of the disease[98]. In addition to a prominent driver of LOAD, an im-mune response subnetwork (module) governed by TYR-OBP, we ident…
has type: Article
is shown at: 10.14288/1.0375819
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: BioMed Central
publisher DOI: 10.1186/s40478-018-0642-x
rights: Attribution 4.0 International (CC BY 4.0)
rights URI: http://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
subject: Alzheimer’s disease
subject: GJA1
subject: Cx43
subject: connexin43
subject: Gene networks
subject: amyloidβ
subject: Astrocyte
type: Text
identifier URI: http://hdl.handle.net/2429/68129