Decoding the Role of Astrocytes in the Entorhinal Cortex in Alzheimer's Disease Using High-Dimensional Single-Nucleus RNA Sequencing Data and Next-Generation Knowledge Discovery Methodologies: Focus on Drugs and Natural Product Remedies for Dementia.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:35295737", "kind": "science-record", "revision": 3, "content_hash": "sha256:175c9dfa5551c036c78427613b0dce202b3d284dc2fa4290331f1fcebec0fc7e", "created_at": "2026-11-01T18:14:04Z", "updated_at": "2026-11-01T21:27:27Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Decoding the Role of Astrocytes in the Entorhinal Cortex in Alzheimer's Disease Using High-Dimensional Single-Nucleus RNA Sequencing Data and Next-Generation Knowledge Discovery Methodologies: Focus on Drugs and Natural Product Remedies for Dementia.", "doi": "10.3389/fphar.2021.720170", "pmid": "35295737", "authors": ["Peter Natesan Pushparaj", "Gauthaman Kalamegam", "Khalid Hussain Wali Sait", "Mahmood Rasool"], "journal": "Frontiers in pharmacology", "year": 2021, "abstract": "Introduction: Alzheimer's disease (AD) is a major cause of the development of cognitive decline and dementia. AD and associated dementias (ADRD) are the major contributors to the enormous burden of morbidity and mortality worldwide. To date, there are no robust therapies to alleviate or cure this debilitating disease. Most drug treatments focus on restoring the normal function of neurons and the cells that cause inflammation, such as microglia in the brain. However, the role of astrocytes, the brain's housekeeping cells, in the development of AD and the initiation of dementia is still not well understood. Objective: To decipher the role of astrocytes in the entorhinal cortex of AD patients using single nuclear RNA sequencing (snRNASeq) datasets from the Single Cell RNA-seq Database for Alzheimer's Disease (scREAD). The datasets were originally derived from astrocytes, isolated from the entorhinal cortex of AD brain and healthy brain to decipher disease-specific signaling pathways as well as drugs and natural products that reverse AD-specific signatures in astrocytes. Methods: We used snRNASeq datasets from the scREAD database originally derived from astrocytes isolated from the entorhinal cortex of AD and healthy brains from the Gene Expression Omnibus (GEO) (GSE138852 and GSE147528) and analyzed them using next-generation knowledge discovery (NGKD) platforms. scREAD is a user-friendly open-source interface available at https://bmbls.bmi.osumc.edu/scread/that enables more discovery-oriented strategies. snRNASeq data and metadata can also be visualized and downloaded via an interactive web application at adsn.ddnetbio.com. Differentially expressed genes (DEGs) for each snRNASeq dataset were analyzed using iPathwayGuide to compare and derive disease-specific pathways, gene ontologies, and in silico predictions of drugs and natural products that regulate AD -specific signatures in astrocytes. In addition, DEGs were analyzed using the L1000FWD and L1000CDS2 signature search programming interfaces (APIs) to identify additional drugs and natural products that mimic or reverse AD-specific gene signatures in astrocytes. Results: We found that PI3K/AKT signaling, Wnt signaling, neuroactive ligand-receptor interaction pathways, neurodegeneration pathways, etc. were significantly impaired in astrocytes from the entorhinal cortex of AD patients. Biological processes such as glutamate receptor signaling pathway, regulation of synapse organization, cell-cell adhesion via plasma membrane adhesion molecules, and chylomicrons were negatively enriched in the astrocytes from the entorhinal cortex of AD patients. Gene sets involved in cellular components such as postsynaptic membrane, synaptic membrane, postsynapse, and synapse part were negatively enriched (p < 0.01). Moreover, molecular functions such as glutamate receptor activity, neurotransmitter receptor activity, and extracellular ligand-gated ion channels were negatively regulated in the astrocytes of the entorhinal cortex of AD patients (p < 0.01). Moreover, the application of NGKD platforms revealed that antirheumatic drugs, vitamin-E, emetine, narciclasine, cephaeline, trichostatin A, withaferin A, dasatinib, etc. can potentially reverse gene signatures associated with AD. Conclusions: The present study highlights an innovative approach to use NGKD platforms to find unique disease-associated signaling pathways and specific synthetic drugs and natural products that can potentially reverse AD and ADRD-associated gene signatures.", "claims": [{"id": "claim-method", "statement": "The iPathwayGuide software used the Impact Analysis Method (IAM) (Draghici et al., 2003; Draghici et al., 2007; Draghici, 2011) to obtain significantly impacted DEGs and pathways compared with the corresponding control group; the p-value computed using Fisher’s method was used to determine the pathway score, and the p-value was adjusted based on the false discovery rate (FDR) (Benjamini and Hochberg, 1995; Benjamini and Yekutieli, 2001). and Bonferroni multiple testing corrections (Bonferroni, 1935).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35295737", "locator": "sections[5] \"2.3 The snRNASeq Data Analysis Using iPathwayGuide\" paragraph 2", "quote": "The iPathwayGuide software used the Impact Analysis Method (IAM) (Draghici et al., 2003; Draghici et al., 2007; Draghici, 2011) to obtain significantly impacted DEGs and pathways compared with the corresponding control group; the p-value computed using Fisher’s method was used to determine the pathway score, and the p-value was adjusted based on the false discovery rate (FDR) (Benjamini and Hochberg, 1995; Benjamini and Yekutieli, 2001). and Bonferroni multiple testing corrections (Bonferroni, 1935)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35295737", "locator": "sections[14] \"Data Availability Statement\" paragraph 2", "quote": "The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material."}], "state": "complete"}, {"id": "claim-target-result", "statement": "PI3K/AKT signaling, Wnt signaling, neuroactive ligand-receptor interaction pathways, and neurodegeneration pathways were impaired in astrocytes from the entorhinal cortex of AD patients.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:35295737", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "We found that PI3K/AKT signaling, Wnt signaling, neuroactive ligand-receptor interaction pathways, neurodegeneration pathways, etc. were significantly impaired in astrocytes from the entorhinal cortex of AD patients."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "PI3K/AKT signaling, Wnt signaling, neuroactive ligand-receptor interaction pathways, and neurodegeneration pathways were impaired in astrocytes from the entorhinal cortex of AD patients.", "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:35295737"], "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": "blocked", "blocked_on": "data:accession_absent", "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": [], "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": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:35295737", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fphar.2021.720170", "sha256": "sha256:dbc288995053963c8621d86120366770693c6a3956b91b38534e5d5885886b08", "bytes": 50613, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fphar.2021.720170", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8918735", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}], "gaps": []}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": null, "specific": null, "label": "Impact Analysis Method (IAM)", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "The iPathwayGuide software used the Impact Analysis Method (IAM) (Draghici et al., 2003; Draghici et al., 2007; Draghici, 2011) to obtain significantly impacted DEGs and pathways compared with the corresponding control group; the p-value computed using Fisher’s method was used to determine the pathway score, and the p-value was adjusted based on the false discovery rate (FDR) (Benjamini and Hochberg, 1995; Benjamini and Yekutieli, 2001). and Bonferroni multiple testing corrections (Bonferroni, 1935)."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "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": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"tier": "R4", "expressible": false, "required_operations": [], "missing_operations": [], "basis": "The reader quoted the method the paper names (Impact Analysis Method (IAM)), but the corpus's method extractor could not map it onto a DSL operation, so the method is published but not expressible."}, "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": "R4", "reachable": false, "accessions": ["GSE138852 and GSE147528"], "resolved_accessions": [], "statements": ["The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material."], "basis": "The paper names GSE138852 and GSE147528, but the accession does not resolve in the repository (no reason recorded), so the data cannot be reached from here. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:35295737"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T17:38:08Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 14708, "completion_tokens": 1495, "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:35295737", "type": "paper", "label": "pmid:35295737"}, {"id": "source:pmid:35295737", "type": "manuscript", "label": "PMID 35295737 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:35295737", "type": "paper", "label": "pmid:35295737"}, {"id": "source:pmid:35295737", "type": "manuscript", "label": "PMID 35295737 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-35295737", "type": "extraction", "used": ["source:pmid:35295737"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "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:35295737", "parent_hash": "sha256:54e577494218482f4ffff7f9f1ec9cc8ac570050e63bffb96b58e64fa5fffd1a", "fork_of": null, "generation": 2}, "gaps": ["execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent"], "assays": [{"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["isease Using High-Dimensional Single-Nucleus RNA Sequencing Data and Next-Generation Knowledge Discovery", "ing (snRNASeq) datasets from the Single Cell RNA-seq Database for Alzheimer's Disease (scREAD). T", "l cortex of AD patients using single nuclear RNA sequencing (snRNASeq) datasets from the Single Cell RNA", "Supplementary Figure S1scREAD. A Single Cell RNA Sequencing Database for Alzheimer’s Disease (Adapted fr"], "order_basis": "paper_text_order:73", "id": "assay:1"}]}