{"doi":"10.1101/2022.07.19.500681","title":"“FDA-approved carbonic anhydrase inhibitors reduce Amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness”","abstract":"Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective cure. Cerebrovascular and neurovascular pathology are early and causal hallmarks of AD, where cerebral amyloid angiopathy (CAA), the deposition of amyloid β (Aβ) at the cerebral vasculature, is present in about 90% of cases. Our previous work has uncovered the protective effect of carbonic anhydrase (CA) inhibition against Aβ-mediated mitochondrial dysfunction, production of reactive oxygen species (ROS) and apoptosis in vascular, glial and neuronal cells in culture. Here, we tested for the first time in a transgenic model of AD and cerebrovascular amyloidosis, the TgSwDI mice, a therapeutic regimen employing the FDA-approved CA inhibitors (CAIs), methazolamide (MTZ) and acetazolamide (ATZ). These drugs are used in humans for glaucoma, high altitude sickness, and other disorders, and can cross the blood-brain barrier. We found that both CAIs were non- toxic, significantly reduced cerebral amyloidosis, vascular, microglial and astrocytic Aβ accumulation, and ameliorated cognition. MTZ and ATZ treatment prevented caspase-3 activation in endothelial cells, microglia and astrocytes, reverted capillary constriction and microhemorrhages, reduced gliosis, and induced glial pro-clearance pathways, which are likely responsible for the reduction of Aβ deposition. Notably, we unveiled a critical new druggable target, revealing that the mitochondrial isozyme CA-VB is specifically upregulated in TgSwDI mouse brains, as well as in human brains of CAA and AD (with CAA) patients. Importantly, Aβ challenge induced CA-VB overexpression in human cerebral endothelial cells, and CA-VB silencing, mimicking CAIs effects, reduced Aβ-mediated endothelial apoptosis. This work paves the way for the application of CAIs in clinical trials for AD and CAA and uncovers CA-VB as a mediator of cerebral amyloid toxicity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":303844,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":308140,"name":"Rebecca Parodi‐Rullán","orcid":"0000-0002-0466-1047","position":1,"is_corresponding":false},{"id":798810,"name":"Rafael Vázquez‐Torres","orcid":null,"position":2,"is_corresponding":false},{"id":490393,"name":"Begona Gamallo‐Lana","orcid":"0009-0004-5687-5778","position":3,"is_corresponding":false},{"id":996720,"name":"Roberto A Guzman‐Hernandez","orcid":null,"position":4,"is_corresponding":false},{"id":647268,"name":"Nicole L Lemon","orcid":null,"position":5,"is_corresponding":false},{"id":996721,"name":"Federica Angiulli","orcid":null,"position":6,"is_corresponding":false},{"id":562420,"name":"Ludovic Debure","orcid":null,"position":7,"is_corresponding":false},{"id":429006,"name":"Marc A. Ilies","orcid":"0000-0003-0694-411X","position":8,"is_corresponding":false},{"id":324215,"name":"Leif Østergaard","orcid":"0000-0003-2930-6997","position":9,"is_corresponding":false},{"id":231338,"name":"Thomas Wısnıewskı","orcid":"0000-0002-3379-8966","position":10,"is_corresponding":false},{"id":996254,"name":"Eugenio Gutiérrez‐Jiménez","orcid":"0000-0002-7509-0720","position":11,"is_corresponding":false},{"id":476721,"name":"Adam C. Mar","orcid":"0000-0002-2095-2936","position":12,"is_corresponding":false},{"id":308141,"name":"Silvia Fossati","orcid":"0000-0002-2047-222X","position":13,"is_corresponding":false},{"id":647269,"name":"Elisa Canepa","orcid":null,"position":0,"is_corresponding":true}],"reference_count":157,"raw_metadata":null,"created_at":"2026-07-19T00:32:28.468841Z","pmid":null,"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":[]}