Integrative Human Genetic and Cellular Analysis of the Pathophysiological Roles of AnxA2 in Alzheimer's Disease.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Antioxidants Pub Date : 2024-10-21 DOI:10.3390/antiox13101274
Lianmeng Ye, Jiazheng Zhao, Zhengpan Xiao, Wenyu Gu, Xiaoxuan Liu, Nuela Manka'a Che Ajuyo, Yi Min, Yechun Pei, Dayong Wang
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Abstract

Alzheimer's disease (AD) is an intractable and progressive neurodegenerative disease. Amyloid beta (Aβ) aggregation is the hallmark of AD. Aβ induces neurotoxicity through a variety of mechanisms, including interacting with membrane receptors to alter downstream signaling, damaging cellular or organelle membranes, interfering with protein degradation and synthesis, and inducing an excessive immune-inflammatory response, all of which lead to neuronal death and other pathological changes associated with AD. In this study, we extracted gene expression profiles from the GSE5281 and GSE97760 microarray datasets in the GEO (Gene Expression Omnibus) database, as well as from the Human Gene Database. We identified differentially expressed genes in the brain tissues of AD patients and healthy persons. Through GO, KEGG, and ROC analyses, annexin A2 (AnxA2) was identified as a putative target gene. Notably, accumulating evidence suggests that intracellular AnxA2 is a key regulator in various biological processes, including endocytosis, transmembrane transport, neuroinflammation, and apoptosis. Thus, we conducted a series of cell biology experiments to explore the biological function of AnxA2 in AD. The results indicate that AnxA2 gene knockdown primarily affects oxidative phosphorylation, cell cycle, AD, protein processing in the endoplasmic reticulum, SNARE interactions in vesicular transport, and autophagy. In SH-SY5Y cells secreting Aβ42, AnxA2 gene knockdown exacerbated Aβ42-induced cytotoxicity, including cell death, intracellular ROS levels, and neuronal senescence, altered cell cycle, and reduced ATP levels, suggesting its critical role in mitochondrial function maintenance. AnxA2 gene knockdown also exacerbated the inhibitory effect of Aβ42 on cell migration. AnxA2 overexpression reduced the inflammatory response induced by Aβ42, while its absence increased pro-inflammatory and decreased anti-inflammatory responses. Furthermore, AnxA2 gene knockdown facilitated apoptosis and decreased autophagy. These results indicated potential pathophysiological roles of AnxA2 in AD.

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对 AnxA2 在阿尔茨海默病中的病理生理作用的人类遗传学和细胞学综合分析。
阿尔茨海默病(AD)是一种难以治愈的进行性神经退行性疾病。淀粉样蛋白β(Aβ)聚集是阿尔茨海默病的标志。Aβ通过多种机制诱导神经毒性,包括与膜受体相互作用改变下游信号传导、破坏细胞膜或细胞器膜、干扰蛋白质降解和合成以及诱导过度免疫炎症反应,所有这些机制都会导致神经元死亡以及与AD相关的其他病理变化。在这项研究中,我们从 GEO(基因表达总库)数据库的 GSE5281 和 GSE97760 微阵列数据集以及人类基因数据库中提取了基因表达谱。我们发现了 AD 患者和健康人脑组织中的差异表达基因。通过GO、KEGG和ROC分析,Annexin A2(AnxA2)被确定为潜在的靶基因。值得注意的是,越来越多的证据表明,细胞内AnxA2是多种生物过程的关键调控因子,包括内吞、跨膜转运、神经炎症和细胞凋亡。因此,我们进行了一系列细胞生物学实验来探索 AnxA2 在 AD 中的生物学功能。结果表明,AnxA2基因敲除主要影响氧化磷酸化、细胞周期、AD、内质网中的蛋白质加工、囊泡转运中的SNARE相互作用以及自噬。在分泌Aβ42的SH-SY5Y细胞中,AnxA2基因敲除会加剧Aβ42诱导的细胞毒性,包括细胞死亡、细胞内ROS水平、神经元衰老、细胞周期改变和ATP水平降低,这表明它在线粒体功能维持中起着关键作用。AnxA2 基因敲除也加剧了 Aβ42 对细胞迁移的抑制作用。AnxA2 基因过表达可降低 Aβ42 诱导的炎症反应,而缺乏 AnxA2 基因则会增加促炎症反应,降低抗炎症反应。此外,AnxA2 基因敲除可促进细胞凋亡并减少自噬。这些结果表明了AnxA2在AD中的潜在病理生理作用。
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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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