Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity.

TitleCarbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity.
Publication TypeJournal Article
Year of Publication2018
AuthorsSolesio ME, Peixoto PM, Debure L, Madamba SM, de Leon MJ, Wisniewski T, Pavlov EV, Fossati S
JournalAging Cell
Volume17
Issue4
Paginatione12787
Date Published2018 08
ISSN1474-9726
KeywordsAcetazolamide, Amyloid beta-Peptides, Carbonic Anhydrase Inhibitors, Dose-Response Relationship, Drug, Endothelium, Vascular, Humans, Methazolamide, Mitochondria, Tumor Cells, Cultured
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 H O 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.

DOI10.1111/acel.12787
Alternate JournalAging Cell
PubMed ID29873184
PubMed Central IDPMC6052473
Grant ListR01 AG022374 / AG / NIA NIH HHS / United States
R01 NS073502 / NS / NINDS NIH HHS / United States
NIRG-12-240372 / / Alzheimer's Association / International
R01 AG012101 / AG / NIA NIH HHS / United States
13SDG16860017 / / American Heart Association / International
/ / Leon Levy Fellowship in Neuroscience / International
/ / Blas Frangione Foundation / International
/ / CIEN-Reina Sofia Foundation / International
P30 AG008051 / AG / NIA NIH HHS / United States
Related Institute: 
Brain Health Imaging Institute (BHII)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065