Title | Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Solesio ME, Peixoto PM, Debure L, Madamba SM, de Leon MJ, Wisniewski T, Pavlov EV, Fossati S |
Journal | Aging Cell |
Volume | 17 |
Issue | 4 |
Pagination | e12787 |
Date Published | 2018 08 |
ISSN | 1474-9726 |
Keywords | Acetazolamide, 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. |
DOI | 10.1111/acel.12787 |
Alternate Journal | Aging Cell |
PubMed ID | 29873184 |
PubMed Central ID | PMC6052473 |
Grant List | R01 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)