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GJA1（连接蛋白 43）是阿尔茨海默病发病机制的关键调节因子。

GJA1 (connexin43) is a key regulator of Alzheimer's disease pathogenesis.

机构信息

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Current address: Denali Therapeutics,, South San Francisco,, CA, 94080, USA.

出版信息

Acta Neuropathol Commun. 2018 Dec 21;6(1):144. doi: 10.1186/s40478-018-0642-x.

DOI:10.1186/s40478-018-0642-x
PMID:30577786
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6303945/
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.

摘要

GJA1（连接蛋白 43）已被预测为与阿尔茨海默病（AD）相关的富含星形胶质细胞的子网络的顶级关键驱动因子。在这项研究中，我们全面检查了来自 AD 和正常对照大脑的 29 个转录组和蛋白质组数据集的 GJA1 表达。我们证明 GJA1 与 AD 淀粉样蛋白和 tau 病理学以及认知功能密切相关。Gja1-/-星形胶质细胞的 RNA 测序分析验证了 Gja1 调节了 AD 中鉴定的子网络，以及许多参与 Aβ代谢的基因。缺乏 Gja1 的星形胶质细胞显示 Apoe 蛋白水平降低，以及 Aβ吞噬作用受损。与此一致的是，与野生型星形胶质细胞共培养的野生型神经元含有更高水平的 Aβ 物质。此外，Gja1-/-星形胶质细胞在 Aβ 应激下具有更强的神经保护作用。我们的结果强调了 GJA1 在 AD 发病机制中的重要性及其作为 AD 有前途的药物靶点进一步研究的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/7e29cf2cad98/40478_2018_642_Fig11_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/7e29cf2cad98/40478_2018_642_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/1a37645ed9c5/40478_2018_642_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/16e3b156ed1e/40478_2018_642_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/0ad652498942/40478_2018_642_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/1d5fa9145c16/40478_2018_642_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/15ca0f8ab45c/40478_2018_642_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/c6d0bbc86fea/40478_2018_642_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/98c647cc4e5d/40478_2018_642_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/c9d472930667/40478_2018_642_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a34/6303945/7e29cf2cad98/40478_2018_642_Fig11_HTML.jpg

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