GJA1 (connexin43) is a key regulator of Alzheimer\u2019s disease pathogenesis

Yuji Kajiwara,Christian C Naus,Kristen J Brennand,Joseph Buxbaum,Eric Schadt,Erming Wang,Bin Zhang,Wun Chey Sin,Minghui Wang

doi:10.1186/s40478-018-0642-x

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.

Highlights

Alzheimer’s disease (AD) reflects multifactorial genetic and environmental perturbations that, in turn, cause pleiotropic changes in molecular networks linking a host of biological processes
We investigated the role of GJA1 in gene networks underlying AD
Our previous study developed a novel network approach capable of integrating clinical and neuropathological data with large-scale genetic and gene expression [98]. This network biology approach led to a novel multiscale network model of late onset Alzheimer’s disease (LOAD), which identified a number of coexpressed gene modules that were strongly associated with AD pathological traits or underwent dramatic disruption of high-order gene-gene interactions [98]

Summary

Introduction

Alzheimer’s disease (AD) reflects multifactorial genetic and environmental perturbations that, in turn, cause pleiotropic changes in molecular networks linking a host of biological processes. By employing an integrative network biology approach to analyze a large-scale genetic and gene expression dataset in late onset Alzheimer’s disease (LOAD), we previously conducted an unbiased identification and prioritization of gene networks associated with clinical and pathological progression of the disease [98]. GJA1, known as connexin (Cx43), is a member of the connexin family of proteins that is highly conserved among vertebrates. Members of the connexin family exist at the plasma membrane as hexameric complexes known as connexons, and function as connexin hemichannels allowing permeability to small molecules and ions [28]. Two connexons at the apposed cell surface of adjacent cells form a trans-dimer called a gap junction channel (GJC). Cx43 functions as a unitary channel (hemichannel) to participate in paracrine communication [17], but this activity is often associated with pathological conditions [21]. Astrocytic gap junctions are critical for neuronal function, as evidenced by the profound

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