Publication Type Academic Article
Authors Solesio M, Peixoto P, Debure L, Madamba S, de Leon M, Wisniewski T, Pavlov E, Fossati S
Journal Aging Cell
Volume 17
Issue 4
Pagination e12787
Date Published 06/05/2018
ISSN 1474-9726
Keywords Acetazolamide, Amyloid beta-Peptides, Carbonic Anhydrase Inhibitors, Endothelium, Vascular, Methazolamide, Mitochondria
Abstract 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 CAIs 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 H2 O2 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 (CAs) in the Aβ-induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA-approved drugs with a well-known profile of brain delivery.
DOI 10.1111/acel.12787
PubMed ID 29873184
PubMed Central ID PMC6052473
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