{"doi":"10.1126/sciadv.ads0505","title":"Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects","abstract":"Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD–associated mutation in TDP-43 ( Tardbp G348C ) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43–deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.","journal":"Science Advances","year":2025,"id":511518,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"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":376713,"name":"Amy L. Kimble","orcid":"0000-0002-0100-4906","position":1,"is_corresponding":false},{"id":1002376,"name":"Emily N. Burrage","orcid":"0000-0002-8263-9662","position":2,"is_corresponding":false},{"id":1370259,"name":"Stephen B. Helming","orcid":null,"position":3,"is_corresponding":false},{"id":1161522,"name":"Jordan D. Tyburski","orcid":"0000-0002-2450-1649","position":4,"is_corresponding":false},{"id":255233,"name":"Nathan K. Leclair","orcid":"0000-0002-0401-2549","position":5,"is_corresponding":false},{"id":1170781,"name":"Omar M. Omar","orcid":"0000-0002-6042-5807","position":6,"is_corresponding":false},{"id":298865,"name":"Aamir Zuberi","orcid":"0000-0003-0252-9760","position":7,"is_corresponding":false},{"id":252298,"name":"Melissa Murphy","orcid":"0000-0001-9906-0713","position":8,"is_corresponding":false},{"id":305930,"name":"Evan R. Jellison","orcid":"0009-0004-2674-1605","position":9,"is_corresponding":false},{"id":779471,"name":"Bo Reese","orcid":"0000-0001-7667-5627","position":10,"is_corresponding":false},{"id":682419,"name":"Xiangyou Hu","orcid":"0000-0002-9083-728X","position":11,"is_corresponding":false},{"id":275066,"name":"Cathleen Lutz","orcid":"0000-0003-2502-1900","position":12,"is_corresponding":false},{"id":492492,"name":"Riqiang Yan","orcid":"0000-0001-7195-7617","position":13,"is_corresponding":false},{"id":376708,"name":"Patrick A. Murphy","orcid":"0000-0002-2956-1042","position":14,"is_corresponding":false},{"id":1161521,"name":"Cheemala Ashok","orcid":"0000-0003-2259-2839","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:47:55.918021Z","pmid":"40238886","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":[]}