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Amyloid beta (A\u03b2) aggregation is the hallmark of AD. A\u03b2 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 A\u03b242, AnxA2 gene knockdown exacerbated A\u03b242-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 A\u03b242 on cell migration. AnxA2 overexpression reduced the inflammatory response induced by A\u03b242, 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.<\/jats:p>","DOI":"10.3390\/antiox13101274","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T12:40:32Z","timestamp":1729514432000},"page":"1274","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Integrative Human Genetic and Cellular Analysis of the Pathophysiological Roles of AnxA2 in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3438-5801","authenticated-orcid":false,"given":"Lianmeng","family":"Ye","sequence":"first","affiliation":[{"name":"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"},{"name":"One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China"},{"name":"Department of Biotechnology, School of Life and Health Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"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"},{"name":"One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China"},{"name":"Department of Biotechnology, School of Life and Health Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengpan","family":"Xiao","sequence":"additional","affiliation":[{"name":"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"},{"name":"One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China"},{"name":"Department of Biotechnology, School of Life and Health Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Gu","sequence":"additional","affiliation":[{"name":"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"},{"name":"One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China"},{"name":"Department of Biotechnology, School of Life and Health Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Min","sequence":"additional","affiliation":[{"name":"One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China"},{"name":"Department of Biotechnology, School of Life and Health Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yechun","family":"Pei","sequence":"additional","affiliation":[{"name":"One Health Cooperative Innovation Center, Hainan University, Haikou 570228, China"},{"name":"Department of Biotechnology, School of Life and Health Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2086-1663","authenticated-orcid":false,"given":"Dayong","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Biopharmaceuticals and Molecular Pharmacology, Key Laboratory of Tropical Biological Resources of 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