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Thome Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020334","name":"Karen Toffler Charitable Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020334","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020334","name":"Karen Toffler Charitable Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020334","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-\u03b2 (A\u03b2) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation in human cerebral microvascular endothelial cells (hCMEC), and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent A\u03b2 induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.<\/jats:p>","DOI":"10.1126\/sciadv.ady1161","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:59:24Z","timestamp":1792000764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial carbonic anhydrase\u2013VB inhibition rescues brain endothelial stress and memory in Alzheimer\u2019s disease models"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5956-4666","authenticated-orcid":true,"given":"Nicole L.","family":"Lemon","sequence":"first","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2906-7797","authenticated-orcid":true,"given":"Elisa","family":"Canepa","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"V\u00e1zquez-Torres","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0466-1047","authenticated-orcid":true,"given":"Rebecca","family":"Parodi-Rull\u00e1n","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9180-4628","authenticated-orcid":true,"given":"Tina","family":"Hirt","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0507-6197","authenticated-orcid":true,"given":"Lisa M.","family":"Petersohn","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9497-3752","authenticated-orcid":true,"given":"Tashnuva","family":"Rifat","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8428-4595","authenticated-orcid":true,"given":"Maryam H.","family":"Abyaneh","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-411X","authenticated-orcid":true,"given":"Marc A.","family":"Ilies","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."},{"name":"Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2047-222X","authenticated-orcid":true,"given":"Silvia","family":"Fossati","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.772278"},{"key":"e_1_3_2_4_2","first-page":"9343514","article-title":"Aducanumab therapy to treat Alzheimer\u2019s Disease: A narrative review","volume":"2022","author":"Beshir S. A.","year":"2022","unstructured":"S. A. Beshir, A. M. Aadithsoorya, A. Parveen, S. S. L. Goh, N. Hussain, V. B. Menon, Aducanumab therapy to treat Alzheimer\u2019s Disease: A narrative review. Int. J. Alzheimers Dis. 2022, 9343514 (2022).","journal-title":"Int. J. Alzheimers Dis."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40001-023-01512-w"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad188"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13512"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12871"},{"key":"e_1_3_2_9_2","first-page":"e12053","article-title":"Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-\u03b2 from the brain and retina with age and Alzheimer\u2019s disease-Opportunities for Therapy","volume":"12","author":"Carare R. O.","year":"2020","unstructured":"R. O. Carare, R. Aldea, N. Agarwal, B. J. Bacskai, I. Bechman, D. Boche, G. Bu, D. Bulters, A. Clemens, S. E. Counts, M. de Leon, P. K. Eide, S. Fossati, S. M. Greenberg, E. Hamel, C. A. Hawkes, M. Koronyo-Hamaoui, A. H. Hainsworth, D. Holtzman, M. Ihara, A. Jefferson, R. N. Kalaria, C. M. Kipps, K. M. Kanninen, V. Leinonen, J. McLaurin, S. Miners, T. Malm, J. A. R. Nicoll, F. Piazza, G. Paul, S. M. Rich, S. Saito, A. Shih, H. Scholtzova, H. Snyder, P. Snyder, F. R. Thormodsson, S. J. van Veluw, R. O. Weller, D. J. Werring, D. Wilcock, M. R. Wilson, B. V. Zlokovic, A. Verma, Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-\u03b2 from the brain and retina with age and Alzheimer\u2019s disease-Opportunities for Therapy. 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Jullienne, R. Quan, J. I. Szu, M. V. Trinh, E. J. Behringer, A. Obenaus, Progressive vascular abnormalities in the aging 3xTg-AD mouse model of Alzheimer\u2019s disease. 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Alber, S. Alladi, H. J. Bae, D. A. Barton, L. A. Beckett, J. M. Bell, S. E. Berman, G. J. Biessels, S. E. Black, I. Bos, G. L. Bowman, E. Brai, A. M. Brickman, B. L. Callahan, R. A. Corriveau, S. Fossati, R. F. Gottesman, D. R. Gustafson, V. Hachinski, K. M. Hayden, A. M. Helman, T. M. Hughes, J. D. Isaacs, A. L. Jefferson, S. C. Johnson, A. Kapasi, S. Kern, J. C. Kwon, J. Kukolja, A. Lee, S. N. Lockhart, A. Murray, K. E. Osborn, M. C. Power, B. R. Price, H. F. M. Rhodius-Meester, J. A. Rondeau, A. C. Rosen, D. L. Rosene, J. A. Schneider, H. Scholtzova, C. E. Shaaban, N. C. B. S. Silva, H. M. Snyder, W. Swardfager, A. M. Troen, S. J. van Veluw, P. Vemuri, A. Wallin, C. Wellington, D. M. Wilcock, S. X. Xie, A. H. Hainsworth, White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities. 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