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Cited by 92Alzheimer's disease research and treatmentsEnzyme function and inhibitionMitochondrial Function and Pathology

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

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Solesio, María E., Peixoto, Pablo M., Debure, Ludovic, Madamba, Stephen M., de Leon, Mony J., Wisniewski, Thomas, Pavlov, Evgeny V., Fossati, Silvia·2018·Aging Cell
DOI 10.1111/acel.12787PMC PMC6052473
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Abstract

Summary: Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease ( AD ). We recently showed that the carbonic anhydrase inhibitor ( CAI ) methazolamide ( MTZ ) prevents amyloid β (Aβ)‐mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide ( ATZ ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAI s selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ . Both MTZ and ATZ prevented mitochondrial membrane depolarization and H 2 O 2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases ( CA s) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy ( CAA ), and paves the way to AD clinical trials for CAI s, FDA ‐approved drugs with a well‐known profile of brain delivery.

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  • CA12 is targeted by carbonic anhydrase inhibitors like acetazolamide, which was shown to reduce Aβ-induced mitochondrial toxicity.

    “Finally, CA12 is targeted by carbonic anhydrase inhibitors like acetazolamide (DB00819), which was shown to reduce Aβ-induced mitochondrial toxicity90.”

    From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [90]

    The Introduction identifies acetazolamide as a carbonic anhydrase inhibitor, and the Discussion reports that it reversed Aβ-induced mitochondrial depolarization and H2O2 production in the study’s cell models. The passages identify other carbonic anhydrase isoforms but do not establish that acetazolamide targets CA12 specifically. Page numbers were not supplied. (LLM, conf=0.88)

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Research works printed but not linked: 48

  1. Abramov, A. Y., Canevari, L., & Duchen, M. R. (2003). Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. Journal of Neuroscience, 23(12), 5088– 5095. 12832532 PMC6741151
  2. Abramov, A. Y., Canevari, L., & Duchen, M. R. (2004). Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture. Biochimica et Biophysica Acta, 1742(1–3), 81– 87. 10.1016/j.bbamcr.2004.09.006. 15590058 · DOI · Paper page
  3. Abramov, A. Y., & Duchen, M. R. (2003). Actions of ionomycin, 4‐Br A23187 and a novel electrogenic Ca2 + ionophore on mitochondria in intact cells. Cell Calcium, 33(2), 101– 112. 12531186
  4. Abramov, A. Y., Fraley, C., Diao, C. T., Winkfein, R., Colicos, M. A., Duchen, M. R., & Pavlov, E. (2007). Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium‐dependent cell death. Proceedings of the National Academy of Sciences of the United States of America, 104(46), 18091– 18096. 10.1073/pnas.0708959104. 17986607 PMC2084301 · DOI
  5. Abramov, A. Y., Scorziello, A., & Duchen, M. R. (2007). Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. Journal of Neuroscience, 27(5), 1129– 1138. 10.1523/JNEUROSCI.4468-06.2007. 17267568 PMC6673180 · DOI
  6. Aggarwal, M., Kondeti, B., & McKenna, R. (2013). Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: A patent review. Expert Opinion on Therapeutic Patents, 23(6), 717– 724. 10.1517/13543776.2013.782394. 23514045 · DOI
  7. Alperin, N., Oliu, C. J., Bagci, A. M., Lee, S. H., Kovanlikaya, I., Adams, D., & Relkin, N. (2014). Low‐dose acetazolamide reverses periventricular white matter hyperintensities in iNPH. Neurology, 82(15), 1347– 1351. 10.1212/WNL.0000000000000313. 24634454 PMC4001191 · DOI
  8. Babcock, D. F., Herrington, J., Goodwin, P. C., Park, Y. B., & Hille, B. (1997). Mitochondrial participation in the intracellular Ca2 + network. Journal of Cell Biology, 136(4), 833– 844. 9049249 PMC2132502
  9. Beal, M. F. (2005). Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment. Neurobiology of Aging, 26(5), 585– 586. https://doi.org/S0197-4580(04)00331-8[pii]. 15708432
  10. Berridge, M. J., Bootman, M. D., & Lipp, P. (1998). Calcium–a life and death signal. Nature, 395(6703), 645– 648. 10.1038/27094. 9790183 · DOI
  11. Boitier, E., Rea, R., & Duchen, M. R. (1999). Mitochondria exert a negative feedback on the propagation of intracellular Ca2 + waves in rat cortical astrocytes. Journal of Cell Biology, 145(4), 795– 808. 10330407 PMC2133193
  12. Celsi, F., Pizzo, P., Brini, M., Leo, S., Fotino, C., Pinton, P., & Rizzuto, R. (2009). Mitochondria, calcium and cell death: A deadly triad in neurodegeneration. Biochimica et Biophysica Acta, 1787(5), 335– 344. 10.1016/j.bbabio.2009.02.021. 19268425 PMC2696196 · DOI
  13. Crandall, E. D., Bidani, A., & Forster, R. E. (1977). Postcapillary changes in blood pH in vivo during carbonic anhydrase inhibition. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology, 43(4), 582– 590. 20440
  14. Drummond, E., Nayak, S., Faustin, A., Pires, G., Hickman, R. A., Askenazi, M., & Wisniewski, T. (2017). Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer's disease. Acta Neuropathologica, 133(6), 933– 954. 10.1007/s00401-017-1691-0. 28258398 PMC5503748 · DOI · Paper page
  15. Fossati, S., Cam, J., Meyerson, J., Mezhericher, E., Romero, I. A., Couraud, P. O., & Rostagno, A. (2010). Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid‐beta variants in cells composing the cerebral vessel walls. FASEB J, 24(1), 229– 241. 10.1096/fj.09-139584[pii]. 19770225 PMC2797039 · DOI
  16. Fossati, S., Ghiso, J., & Rostagno, A. (2012a). Insights into caspase‐mediated apoptotic pathways induced by amyloid‐beta in cerebral microvascular endothelial cells. Neuro‐Degenerative Diseases, 10(1–4), 324– 328. 10.1159/000332821. 22156599 PMC3363348 · DOI
  17. Fossati, S., Ghiso, J., & Rostagno, A. (2012b). TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer's Abeta. Cell Death & Disease, 3, e321 10.1038/cddis.2012.55[pii]. 22695614 PMC3388229 · DOI
  18. Fossati, S., Giannoni, P., Solesio, M. E., Cocklin, S. L., Cabrera, E., Ghiso, J., & Rostagno, A. (2016). The carbonic anhydrase inhibitor methazolamide prevents amyloid beta‐induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain. Neurobiology of Diseases, 86, 29– 40. 10.1016/j.nbd.2015.11.006. PMC4713307 26581638 · DOI
  19. Fossati, S., Todd, K., Sotolongo, K., Ghiso, J., & Rostagno, A. (2013). Differential contribution of isoaspartate post‐translational modifications to the fibrillization and toxic properties of amyloid‐beta and the asparagine 23 Iowa mutation. Biochemical Journal, 456, 347– 360 10.1042/BJ20130652[pii]. 24028142 PMC4467552 · DOI
  20. Garwood, C., Faizullabhoy, A., Wharton, S. B., Ince, P. G., Heath, P. R., Shaw, P. J., … Brayne, C. (2013). Calcium dysregulation in relation to Alzheimer‐type pathology in the ageing brain. Neuropathology and Applied Neurobiology, 39(7), 788– 799. 10.1111/nan.12033. 23421725 · DOI · Paper page
  21. Ghandour, M. S., Parkkila, A. K., Parkkila, S., Waheed, A., & Sly, W. S. (2000). Mitochondrial carbonic anhydrase in the nervous system: Expression in neuronal and glial cells. Journal of Neurochemistry, 75(5), 2212– 2220. 11032910
  22. Granatiero, V., Giorgio, V., Cali, T., Patron, M., Brini, M., Bernardi, P., & Rizzuto, R. (2015). Reduced mitochondrial Ca transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase. Cell Death and Differentiation, 23(2), 231 10.1038/cdd.2015.84. 26206091 PMC4716301 · DOI
  23. Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., & Smith, M. A. (2001). Mitochondrial abnormalities in Alzheimer's disease. Journal of Neuroscience, 21(9), 3017– 3023. 11312286 PMC6762571
  24. Huang, L., Yang, Q., Zhang, L., Chen, X., Huang, Q., & Wang, H. (2010). Acetazolamide improves cerebral hemodynamics in CADASIL. Journal of the Neurological Sciences, 292(1–2), 77– 80. 10.1016/j.jns.2010.01.023. 20227091 · DOI
  25. Jiang, S., Wang, F., Zhu, S., Zhang, X., Guo, Z., Li, R., & Xu, Q. (2013). Preformulation study of methazolamide for topical ophthalmic delivery: Physicochemical properties and degradation kinetics in aqueous solutions. International Journal of Pharmaceutics, 448(2), 390– 393. 10.1016/j.ijpharm.2013.03.018. 23541985 · DOI
  26. Kamegawa, A., Hiroaki, Y., Tani, K., & Fujiyoshi, Y. (2016). Two‐dimensional crystal structure of aquaporin‐4 bound to the inhibitor acetazolamide. Microscopy (Oxf), 65(2), 177– 184. 10.1093/jmicro/dfv368. 26908838 PMC4817316 · DOI
  27. Kaminsky, Y. G., & Kosenko, E. A. (2008). Effects of amyloid‐beta peptides on hydrogen peroxide‐metabolizing enzymes in rat brain in vivo. Free Radical Research, 42(6), 564– 573. 10.1080/10715760802159057. 18569014 · DOI
  28. MacLennan, D. H., & Wong, P. T. (1971). Isolation of a calcium‐sequestering protein from sarcoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America, 68(6), 1231– 1235. 4256614 PMC389160
  29. Mancuso, M., Coppede, F., Murri, L., & Siciliano, G. (2007). Mitochondrial cascade hypothesis of Alzheimer's disease: Myth or reality? Antioxidants & Redox Signaling, 9(10), 1631– 1646. 10.1089/ars.2007.1761. 17887917 · DOI
  30. Meldrum, N. U., & Roughton, F. J. (1933). Carbonic anhydrase. Its preparation and properties. The Journal of Physiology, 80(2), 113– 142. 16994489 PMC1394121
  31. Milton, N. G. (2004). Role of hydrogen peroxide in the aetiology of Alzheimer's disease: Implications for treatment. Drugs and Aging, 21(2), 81– 100. 14960126
  32. Moreira, P. I., Carvalho, C., Zhu, X., Smith, M. A., & Perry, G. (2010). Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochimica et Biophysica Acta, 1802(1), 2– 10. 10.1016/j.bbadis.2009.10.006. 19853658 · DOI · Paper page
  33. Newington, J. T., Pitts, A., Chien, A., Arseneault, R., Schubert, D., & Cumming, R. C. (2011). Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect. PLoS One, 6(4), e19191 10.1371/journal.pone.0019191. 21541279 PMC3082554 · DOI
  34. Pollard, A., Shephard, F., Freed, J., Liddell, S., & Chakrabarti, L. (2016). Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration. Aging (Albany NY), 8(10), 2425– 2436. 10.18632/aging.101064. 27743511 PMC5115898 · DOI
  35. Price, T. O., Eranki, V., Banks, W. A., Ercal, N., & Shah, G. N. (2012). Topiramate treatment protects blood‐brain barrier pericytes from hyperglycemia‐induced oxidative damage in diabetic mice. Endocrinology, 153(1), 362– 372. 10.1210/en.2011-1638. 22109883 PMC3249670 · DOI
  36. Revesz, T., Holton, J. L., Lashley, T., Plant, G., Frangione, B., Rostagno, A., & Ghiso, J. (2009). Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathologica, 118(1), 115– 130. 10.1007/s00401-009-0501-8. 19225789 PMC2844092 · DOI
  37. Shah, G. N., Morofuji, Y., Banks, W. A., & Price, T. O. (2013). High glucose‐induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes. Biochemical and Biophysical Research Communications, 440(2), 354– 358. 10.1016/j.bbrc.2013.09.086. 24076121 PMC3875343 · DOI
  38. Singh, M., Sharma, H., & Singh, N. (2007). Hydrogen peroxide induces apoptosis in HeLa cells through mitochondrial pathway. Mitochondrion, 7(6), 367– 373. 10.1016/j.mito.2007.07.003. 17855174 · DOI
  39. Smithen, M., Elustondo, P. A., Winkfein, R., Zakharian, E., Abramov, A. Y., & Pavlov, E. (2013). Role of polyhydroxybutyrate in mitochondrial calcium uptake. Cell Calcium, 54(2), 86– 94. 10.1016/j.ceca.2013.04.006. 23702223 PMC3761873 · DOI
  40. Solesio, M. E., Prime, T. A., Logan, A., Murphy, M. P., Del Mar Arroyo‐Jimenez, M., Jordan, J., & Galindo, M. F. (2013). The mitochondria‐targeted anti‐oxidant MitoQ reduces aspects of mitochondrial fission in the 6‐OHDA cell model of Parkinson's disease. Biochimica et Biophysica Acta, 1832(1), 174– 182. 10.1016/j.bbadis.2012.07.009. 22846607 · DOI
  41. Solesio, M. E., Saez‐Atienzar, S., Jordan, J., & Galindo, M. F. (2012). Characterization of mitophagy in the 6‐hydoxydopamine Parkinson's disease model. Toxicological Sciences, 129(2), 411– 420. 10.1093/toxsci/kfs218. 22821850 · DOI
  42. Solesio, M. E., Saez‐Atienzar, S., Jordan, J., & Galindo, M. F. (2013). 3‐Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activating the mitochondrial fission pathway. British Journal of Pharmacology, 168(1), 63– 75. 10.1111/j.1476-5381.2012.01994.x. 22509855 PMC3570004 · DOI
  43. Supuran, C. T. (2008). Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery, 7(2), 168– 181. 10.1038/nrd2467. 18167490 · DOI
  44. Swerdlow, R. H., & Khan, S. M. (2009). The Alzheimer's disease mitochondrial cascade hypothesis: An update. Experimental Neurology, 218(2), 308– 315. 10.1016/j.expneurol.2009.01.011[pii]. 19416677 PMC2710413 · DOI
  45. Tabner, B. J., El‐Agnaf, O. M., Turnbull, S., German, M. J., Paleologou, K. E., Hayashi, Y., & Allsop, D. (2005). Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. Journal of Biological Chemistry, 280(43), 35789– 35792. 10.1074/jbc.C500238200. 16141213 · DOI
  46. Wang, X., Figueroa, B. E., Stavrovskaya, I. G., Zhang, Y., Sirianni, A. C., Zhu, S., & Friedlander, R. M. (2009). Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke, 40(5), 1877– 1885. 10.1161/STROKEAHA.108.540765[pii]. 19299628 PMC2674528 · DOI
  47. Wang, X., Zhu, S., Pei, Z., Drozda, M., Stavrovskaya, I. G., Del Signore, S. J., & Friedlander, R. M. (2008). Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease. Journal of Neuroscience, 28(38), 9473– 9485. 10.1523/JNEUROSCI.1867-08.2008[pii]. 18799679 PMC2632939 · DOI
  48. Wright, A., Brearey, S., & Imray, C. (2008). High hopes at high altitudes: Pharmacotherapy for acute mountain sickness and high‐altitude cerebral and pulmonary oedema. Expert Opinion on Pharmacotherapy, 9(1), 119– 127. 10.1517/14656566.9.1.119. 18076343 · DOI

Cited by

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Authors
Solesio, M. E., Peixoto, P. M., Debure, L., Madamba, S. M., de Leon, M. J., Wisniewski, T., Pavlov, E. V., & Fossati, S.
Affiliations
  • New York University (US)
  • Baruch College (US)
  • NYU Langone Health (US)
  • Department of Psychiatry New York University School of Medicine New York New York
  • Department of Neurology Center for Cognitive Neurology New York University School of Medicine New York New York
Corresponding author
Fossati, Silvia
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2018-06-05
Volume
17
Issue
4
Pages
e12787-e12787
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.12787
PMC
PMC6052473
OpenAlex
W2806856966
Cited by
92
References
5
Citations by year
2026: 10 · 2025: 16 · 2024: 14 · 2023: 7 · 2022: 14 · 2021: 18 · 2020: 7 · 2019: 6
FWCI
5.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CUNY Academic Works (City University of New York) (submittedVersion, cc-by)
Funders
  • Alzheimer's Association (NIRG‐12‐240372)
  • American Heart Association (13SDG16860017)
  • National Institutes of Health (AG008051, NS073502, AG13616, AG022374, AG12101, AG057570)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
carbonic anhydrase inhibitors, methazolamide, acetazolamide, amyloid-beta, mitochondrial dysfunction, Alzheimer's disease, cerebral amyloid angiopathy, mitochondrial depolarization, hydrogen peroxide production, apoptosis, calcium homeostasis, drug repurposing
MeSH terms
Acetazolamide, Carbonic Anhydrase Inhibitors, Dose-Response Relationship, Drug, Endothelium, Vascular, Humans, Methazolamide, Mitochondria, Tumor Cells, Cultured, Amyloid beta-Peptides

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