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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:39456526", "kind": "science-record", "revision": 4, "content_hash": "sha256:5c4e8a00ea91f518b4e303ae7f59533ea595fc87dc7f15d9f52571426a2454f6", "created_at": "2026-11-01T20:29:43Z", "updated_at": "2026-11-01T22:55:29Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Integrative Human Genetic and Cellular Analysis of the Pathophysiological Roles of AnxA2 in Alzheimer's Disease.", "doi": "10.3390/antiox13101274", "pmid": "39456526", "authors": ["Lianmeng Ye", "Jiazheng Zhao", "Zhengpan Xiao", "Wenyu Gu", "Xiaoxuan Liu", "Nuela Manka'a Che Ajuyo", "Yi Min", "Yechun Pei", "Dayong Wang"], "journal": "Antioxidants (Basel, Switzerland)", "year": 2024, "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.", "claims": [{"id": "claim-data-access", "statement": "Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39456526", "locator": "sections[40] \"notes\" paragraph 1", "quote": "Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Through GO, KEGG, and ROC analyses, annexin A2 (AnxA2) was identified as a putative target gene.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:39456526", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Through GO, KEGG, and ROC analyses, annexin A2 (AnxA2) was identified as a putative target gene."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Through GO, KEGG, and ROC analyses, annexin A2 (AnxA2) was identified as a putative target gene.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:39456526"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE5281"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE5281"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:39456526", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3390/antiox13101274", "sha256": "sha256:243414003a5a96662e991019992bdff7bf052ef48bde3fabbaa1cf2afe1f39b7", "bytes": 56296, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3390/antiox13101274", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC11504888", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE5281", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE5281", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE5281", "version": null, "note": "Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM119615", "GSM119616", "GSM119617", "GSM119618", "GSM119619", "GSM119620", "GSM119621", "GSM119622", "GSM119623", "GSM119624", "GSM119625", "GSM119626", "GSM119627", "GSM119628", "GSM119629", "GSM119630", "GSM119631", "GSM119632", "GSM119633", "GSM119634", "GSM119635", "GSM119636", "GSM119637", "GSM119638", "GSM119639", "GSM119640", "GSM119641", "GSM119642", "GSM119643", "GSM119644", "GSM119645", "GSM119646", "GSM119647", "GSM119648", "GSM119649", "GSM119650", "GSM119651", "GSM119652", "GSM119653", "GSM119654", "GSM119655", "GSM119656", "GSM119657", "GSM119658", "GSM119659", "GSM119660", "GSM119661", "GSM119662", "GSM119663", "GSM119664", "GSM119665", "GSM119666", "GSM119667", "GSM119668", "GSM119669", "GSM119670", "GSM119671", "GSM119672", "GSM119673", "GSM119674", "GSM119675", "GSM119676", "GSM119677", "GSM119678", "GSM119679", "GSM119680", "GSM119681", "GSM119682", "GSM119683", "GSM119684", "GSM119685", "GSM119686", "GSM119687", "GSM119688", "GSM238763", "GSM238790", "GSM238791", "GSM238792", "GSM238793", "GSM238794", "GSM238795", "GSM238796", "GSM238797", "GSM238798", "GSM238799", "GSM238800", "GSM238801", "GSM238802", "GSM238803", "GSM238804", "GSM238805", "GSM238806", "GSM238807", "GSM238808", "GSM238809", "GSM238810", "GSM238811", "GSM238812", "GSM238813", "GSM238815", "GSM238816", "GSM238817", "GSM238818", "GSM238819", "GSM238820", "GSM238821", "GSM238822", "GSM238823", "GSM238824", "GSM238825", "GSM238826", "GSM238827", "GSM238834", "GSM238835", "GSM238837", "GSM238838", "GSM238839", "GSM238840", "GSM238841", "GSM238842", "GSM238843", "GSM238844", "GSM238845", "GSM238846", "GSM238847", "GSM238848", "GSM238851", "GSM238854", "GSM238855", "GSM238856", "GSM238857", "GSM238858", "GSM238860", "GSM238861", "GSM238862", "GSM238863", "GSM238864", "GSM238865", "GSM238867", "GSM238868", "GSM238870", "GSM238871", "GSM238872", "GSM238873", "GSM238874", "GSM238875", "GSM238877", "GSM238941", "GSM238942", "GSM238943", "GSM238944", "GSM238945", "GSM238946", "GSM238947", "GSM238948", "GSM238949", "GSM238951", "GSM238952", "GSM238953", "GSM238955", "GSM238963"], "sample_count": 161, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Alzheimer's disease and the normal aged brain (steph-affy-human-433773)", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE97760", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE97760", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE97760", "version": null, "note": "Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM2577046", "GSM2577047", "GSM2577048", "GSM2577049", "GSM2577050", "GSM2577051", "GSM2577052", "GSM2577053", "GSM2577054", "GSM2577055", "GSM2577056", "GSM2577057", "GSM2577058", "GSM2577059", "GSM2577060", "GSM2577061", "GSM2577062", "GSM2577063", "GSM2577064"], "sample_count": 19, "group_sizes": null, "group_sizes_basis": null, "platform": "16699", "taxon": "Homo sapiens", "title": "Blood genome-wide gene expression microarray profiles in female patients with advanced Alzheimer's Disease and healthy controls", "resolution_checked_at": "2026-11-01T18:06:44Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE5281 not downloaded", "asset:data:geo:GSE5281 licence not read", "asset:data:geo:GSE97760 not downloaded", "asset:data:geo:GSE97760 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "differential_expression", "specific": "limma_voom", "label": "Differential expression analysis", "dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["count_matrix_with_condition"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "The Bioconductor linear models for the microarray data package (http://www.bioconductor.org/packages/release/bioc/html/limma.html, accessed on 26 August 2022) were used to identify DEGs by comparing the expression values between AD and the control tissues."}}, {"id": "method-2", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "ANOVA"}}, {"id": "method-3", "family": "network_analysis", "specific": "pathway_enrichment", "label": "Network / pathway analysis", "dsl_operations": ["pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.8, "band": "high", "quote": "pathway enrichment"}}], "targets": [], "gaps": ["method.reader_differs_from_extractor"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: limma_voom."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE5281", "GSE97760"], "resolved_accessions": ["GSE5281", "GSE97760"], "statements": ["Data Availability StatementThe datasets generated and/or analyzed during the current study are available in the following public repositories: Gene expression profiles (GSE5281 and GSE97760) were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/, accessed on 26 August 2022). The gene-related information used in this study was retrieved from GeneCard: The Human Gene Database (https://www.genecards.org/, accessed on 26 August 2022). All relevant datasets are publicly accessible."], "basis": "The paper names GSE5281, GSE97760 in GEO (Gene Expression Omnibus) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "assets": ["source:pmid:39456526", "data:geo:GSE5281"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE5281"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:36:57Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 16082, "completion_tokens": 2419, "cached_tokens": 256}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:39456526", "type": "paper", "label": "pmid:39456526"}, {"id": "source:pmid:39456526", "type": "manuscript", "label": "PMID 39456526 full text"}, {"id": "data:geo:GSE5281", "type": "dataset", "label": "GEO GSE5281"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:39456526", "type": "paper", "label": "pmid:39456526"}, {"id": "source:pmid:39456526", "type": "manuscript", "label": "PMID 39456526 full text"}, {"id": "data:geo:GSE5281", "type": "dataset", "label": "GEO GSE5281"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-39456526", "type": "extraction", "used": ["source:pmid:39456526"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE5281", "type": "accession_resolution", "used": ["data:geo:GSE5281"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:39456526", "parent_hash": "sha256:b87c2f326fd29611b43f6aeb3f157ff205a6df91ada88e722767920a774e8f3b", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE5281 licence not read", "asset:data:geo:GSE5281 not downloaded", "asset:data:geo:GSE97760 licence not read", "asset:data:geo:GSE97760 not downloaded", "execution.not_run", "method.reader_differs_from_extractor", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["nsmembrane transport, neuroinflammation, and apoptosis. Thus, we conducted a series of cell biology", "urthermore, AnxA2 gene knockdown facilitated apoptosis and decreased autophagy. These results indic"], "order_basis": "paper_text_order:1157", "id": "assay:1"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["in AD. The results indicate that AnxA2 gene knockdown primarily affects oxidative phosphorylation,", "In SH-SY5Y cells secreting Aβ42, AnxA2 gene knockdown exacerbated Aβ42-induced cytotoxicity, inclu", "tochondrial function maintenance. AnxA2 gene knockdown also exacerbated the inhibitory effect of Aβ", "lammatory responses. Furthermore, AnxA2 gene knockdown facilitated apoptosis and decreased autophag"], "order_basis": "paper_text_order:1313", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ns in vesicular transport, and autophagy. In SH-SY5Y cells secreting Aβ42, AnxA2 gene knockdown e", "elatin made from deep-sea fish skin and then cultured in a CO2 incubator at 37 °C. When the cultured", "ltured in a CO2 incubator at 37 °C. When the cultured cells reached 80% confluency, they were used", "statistically significant. 2.9. Cell Culture SH-SY5Y and HMC3 cells taken out from the liquid nit"], "order_basis": "paper_text_order:1493", "id": "assay:3"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["cells secreting Aβ42 (Figure 2), followed by Western blotting and transcriptome sequencing. Interestingly,"], "order_basis": "paper_text_order:3695", "id": "assay:4"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The Bioconductor linear models for the microarray data package (http://www.bioconductor.org/packages/release/bioc/html/limma.html, accessed on 26 August 2022) were used to identify DEGs by comparing the expression values between AD and the control tissues."], "order_basis": "consumes_earlier_output", "id": "assay:5"}]}