Ye Lianmeng, Zhao Jiazheng, Xiao Zhengpan, Gu Wenyu, Liu Xiaoxuan, Ajuyo Nuela Manka'a Che, Min Yi, Pei Yechun, Wang Dayong
Laboratory of Biopharmaceuticals and Molecular Pharmacology, Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China.
Antioxidants (Basel). 2024 Oct 21;13(10):1274. doi: 10.3390/antiox13101274.
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.
阿尔茨海默病（AD）是一种难治性进行性神经退行性疾病。β淀粉样蛋白（Aβ）聚集是AD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以改变下游信号传导、损伤细胞膜或细胞器膜、干扰蛋白质降解和合成以及诱导过度的免疫炎症反应，所有这些都会导致神经元死亡以及与AD相关的其他病理变化。在本研究中，我们从基因表达综合数据库（GEO）中的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。我们鉴定了AD患者和健康人脑组织中的差异表达基因。通过基因本体（GO）、京都基因与基因组百科全书（KEGG）和受试者工作特征（ROC）分析，膜联蛋白A2（AnxA2）被确定为一个假定的靶基因。值得注意的是，越来越多的证据表明，细胞内AnxA2是包括内吞作用、跨膜运输、神经炎症和细胞凋亡在内的各种生物学过程中的关键调节因子。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基因敲低主要影响氧化磷酸化、细胞周期、AD、内质网中的蛋白质加工、囊泡运输中的SNARE相互作用以及自噬。在分泌Aβ42的SH-SY5Y细胞中，AnxA2基因敲低加剧了Aβ42诱导的细胞毒性，包括细胞死亡、细胞内活性氧水平和神经元衰老，改变了细胞周期并降低了ATP水平，表明其在维持线粒体功能中起关键作用。AnxA2基因敲低还加剧了Aβ42对细胞迁移的抑制作用。AnxA2过表达减少了Aβ42诱导的炎症反应，而其缺失则增加了促炎反应并降低了抗炎反应。此外，AnxA2基因敲低促进了细胞凋亡并减少了自噬。这些结果表明AnxA2在AD中具有潜在的病理生理作用。
