Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. Academic Article uri icon

Overview

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.

publication date

  • June 5, 2018

Research

keywords

  • Acetazolamide
  • Amyloid beta-Peptides
  • Carbonic Anhydrase Inhibitors
  • Endothelium, Vascular
  • Methazolamide
  • Mitochondria

Identity

PubMed Central ID

  • PMC6052473

Scopus Document Identifier

  • 85050275023

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2008.01.003[pii]

PubMed ID

  • 29873184

Additional Document Info

volume

  • 17

issue

  • 4