title: 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.
abstract: Mitochondrial dysfunction has been recognized as an early event in Alzheimer's disease (AD) pathology, preceding and inducing neurodegeneration and memory loss. The presence of cytochrome c (CytC) released from the mitochondria into the cytoplasm is often detected after acute or chronic neurodegenerative insults, including AD. The carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) was identified among a library of drugs as an inhibitor of CytC release and proved to be neuroprotective in Huntington's disease and stroke models. Here, using neuronal and glial cell cultures, in addition to an acute model of amyloid beta (Aβ) toxicity, which replicates by intra-hippocampal injection the consequences of interstitial and cellular accumulation of Aβ, we analyzed the effects of MTZ on neuronal and glial degeneration induced by the Alzheimer's amyloid. MTZ prevented DNA fragmentation, CytC release and activation of caspase 9 and caspase 3 induced by Aβ in neuronal and glial cells in culture through the inhibition of mitochondrial hydrogen peroxide production. Moreover, intraperitoneal administration of MTZ prevented neurodegeneration induced by intra-hippocampal Aβ injection in the mouse brain and was effective at reducing caspase 3 activation in neurons and microglia in the area surrounding the injection site. Our results, delineating the molecular mechanism of action of MTZ against Aβ-mediated mitochondrial dysfunction and caspase activation, and demonstrating its efficiency in a model of acute amyloid-mediated toxicity, provide the first combined in vitro and in vivo evidence supporting the potential of a new therapy employing FDA-approved CAIs in AD.
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States. Electronic address: silvia.fossati@nyumc.org.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fossati
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannoni
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Solesio
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Cocklin
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States.
authors.forename: Erwin
authors.initials: E
authors.lastname: Cabrera
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States; Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States. Electronic address: agueda.rostagno@nyumc.org.
authors.forename: Agueda
authors.initials: A
authors.lastname: Rostagno
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008704:Methazolamide / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*
chemical_list: D016229:Amyloid beta-Peptides; D002257:Carbonic Anhydrase Inhibitors; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D008704:Methazolamide
keywords: Alzheimer's disease; Amyloid; Carbonic anhydrase inhibitor; Caspase activation; Hippocampus; Hydrogen peroxide; Methazolamide; Microglia; Mitochondria; Neuron