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Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

María E Solesio1, Pablo M Peixoto2, Ludovic Debure3

  • 1Department of Basic Sciences, New York University College of Dentistry, New York, New York.

Aging Cell
|June 7, 2018
PubMed

Insights

Carbonic anhydrase inhibitors (CAIs) like methazolamide and acetazolamide protect brain cells from amyloid-beta toxicity by preserving mitochondrial function. These FDA-approved drugs show promise for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) clinical trials.

Area of Science:

  • Neuroscience
  • Mitochondrial Biology
  • Pharmacology

Background:

  • Mitochondrial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis.
  • Amyloid-beta (Aβ) peptides trigger apoptosis and mitochondrial damage in neuronal and vascular cells.
  • Carbonic anhydrase inhibitors (CAIs) have shown potential in preventing Aβ-mediated apoptosis.

Purpose of the Study:

  • To investigate the protective effects and mitochondrial mechanisms of CAIs, specifically methazolamide (MTZ) and acetazolamide (ATZ), against Aβ-induced cellular toxicity.
  • To elucidate the role of carbonic anhydrases (CAs) in Aβ-induced mitochondrial dysfunction relevant to AD and cerebral amyloid angiopathy (CAA).

Main Methods:

  • Neuronal and cerebral vascular cells were challenged with amyloid-beta (Aβ).
  • The effects of methazolamide (MTZ) and acetazolamide (ATZ) on mitochondrial function, including membrane potential and hydrogen peroxide generation, were assessed.
  • Cellular pH and ATP production were monitored to evaluate metabolic effects.

Main Results:

  • CAIs selectively inhibited Aβ-induced mitochondrial dysfunction pathways without impacting overall metabolic function.
  • Both MTZ and ATZ prevented mitochondrial membrane depolarization and reactive oxygen species (ROS) generation.
  • Acetazolamide (ATZ) demonstrated efficacy at concentrations 10-fold lower than MTZ.
  • The drugs did not significantly alter intracellular pH, ATP production, or calcium homeostasis.

Conclusions:

  • Carbonic anhydrases play a significant role in Aβ-induced mitochondrial toxicity relevant to AD and CAA.
  • CAIs represent a promising therapeutic strategy for AD and CAA, warranting further clinical investigation.
  • FDA-approved CAIs offer a potential advantage due to their established safety and brain penetrance.
Keywords:
Alzheimer's diseaseacetazolamideamyloid βcarbonic anhydrase inhibitorsmethazolamidemitochondria

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