期刊
AGING CELL
卷 17, 期 4, 页码 -出版社
WILEY
DOI: 10.1111/acel.12787
关键词
Alzheimer's disease; amyloid beta; carbonic anhydrase inhibitors; acetazolamide; methazolamide; mitochondria
资金
- Leon Levy Fellowship in Neuroscience
- Alzheimer's Association [NIRG-12-240372]
- Blas Frangione Foundation
- CIEN-Reina Sofia Foundation
- American Heart Association [13SDG16860017]
- NIH [AG008051, NS073502, AG13616, AG022374, AG12101, AG057570]
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 beta (A beta)-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 A beta, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by A beta, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 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 A beta-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.
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