Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Abstract

Summary 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 CAI s 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 2 O 2 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 ( CA s) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy ( CAA ), and paves the way to AD clinical trials for CAI s, FDA ‐approved drugs with a well‐known profile of brain delivery.