{"doi":"10.1101/2025.09.26.678918","title":"Inflammatory reprogramming of human brain endothelial cells compromises blood–brain barrier integrity in Alzheimer’s disease","abstract":"Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD), yet the endothelial gene-regulatory programs involved remain incompletely understood. We integrate postmortem human single-nucleus transcriptomics with iPSC-based BBB models to define a conserved, inflammation-driven pathway that compromises barrier integrity. We identify an NF-κB-associated endothelial gene module endoM2 that is elevated in AD, inversely correlated with cognition, and enriched for inflammation and endothelial-to-mesenchymal transition signatures. Cytokine stimulation of iPSC-derived brain endothelial cells induces morphological remodeling, lipid accumulation, junctional disruption, and transcriptomic shifts that mirror endoM2. A targeted drug screen identifies the NF-κB inhibitor BAY11-7082 as protective against cytokine-induced changes. In our perfusable iPSC-derived BBB-Chip that recapitulates human BBB signatures, single-cell profiling reveals inflammatory endothelial state-specific programs reflecting those in AD brains and demonstrates that BAY11-7082 suppresses cytokine-triggered dysfunction and reverses inflammation-associated gene activation. Together, these findings position cerebrovascular inflammation as a therapeutic target to preserve BBB integrity in AD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":576152,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":647708,"name":"Rezaul Islam","orcid":"0000-0003-4037-3293","position":1,"is_corresponding":false},{"id":71422,"name":"Oisín King","orcid":null,"position":2,"is_corresponding":false},{"id":454241,"name":"Aaron Choi","orcid":null,"position":3,"is_corresponding":false},{"id":1456854,"name":"Eulim Kang","orcid":null,"position":4,"is_corresponding":false},{"id":1484747,"name":"Masaki Nakano","orcid":"0000-0003-2273-9589","position":5,"is_corresponding":false},{"id":1485106,"name":"Anjanet Tuyeras","orcid":null,"position":6,"is_corresponding":false},{"id":57298,"name":"Maeesha Tasnim Naomi","orcid":null,"position":7,"is_corresponding":false},{"id":1484748,"name":"An Ngo","orcid":"0000-0002-0565-3233","position":8,"is_corresponding":false},{"id":40699,"name":"Alan Jiang","orcid":"0000-0003-1972-3930","position":9,"is_corresponding":false},{"id":40702,"name":"Nhat Truong","orcid":null,"position":10,"is_corresponding":false},{"id":40696,"name":"Emre Agbas","orcid":null,"position":11,"is_corresponding":false},{"id":1456438,"name":"Clara Cruz-Ramos","orcid":"0000-0001-6050-5885","position":12,"is_corresponding":false},{"id":40703,"name":"Colin Staab","orcid":null,"position":13,"is_corresponding":false},{"id":17179,"name":"Tak Ko","orcid":null,"position":14,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":15,"is_corresponding":false},{"id":40707,"name":"Alice E. Stanton","orcid":"0000-0002-8981-0629","position":16,"is_corresponding":false},{"id":40706,"name":"Robert Langer","orcid":"0000-0003-4255-0492","position":17,"is_corresponding":false},{"id":11618,"name":"Li-Huei Tsai","orcid":"0000-0003-1262-0592","position":18,"is_corresponding":false},{"id":40709,"name":"Rebecca L. Pinals","orcid":"0000-0002-5369-2317","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:56.636458Z","pmid":"41040406","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}