Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

María E. Solesio, Pablo M. Peixoto, Ludovic Debure, Stephen M. Madamba, Mony J. de Leon, Thomas Wisniewski, Evgeny Pavlov, Silvia Fossati

Research output: Contribution to journalArticle

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 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 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.

Original languageEnglish (US)
Article numbere12787
JournalAging Cell
Volume17
Issue number4
DOIs
StatePublished - Aug 1 2018

Fingerprint

Methazolamide
Carbonic Anhydrases
Amyloid
Acetazolamide
Carbonic Anhydrase Inhibitors
Alzheimer Disease
Cerebral Amyloid Angiopathy
Brain
Mitochondrial Membranes
Pharmaceutical Preparations
Blood Vessels
Homeostasis
Adenosine Triphosphate
Clinical Trials
Apoptosis
Calcium
Inhibition (Psychology)

Keywords

  • acetazolamide
  • Alzheimer's disease
  • amyloid β
  • carbonic anhydrase inhibitors
  • methazolamide
  • mitochondria

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Solesio, M. E., Peixoto, P. M., Debure, L., Madamba, S. M., de Leon, M. J., Wisniewski, T., ... Fossati, S. (2018). Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. Aging Cell, 17(4), [e12787]. https://doi.org/10.1111/acel.12787

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. / Solesio, María E.; Peixoto, Pablo M.; Debure, Ludovic; Madamba, Stephen M.; de Leon, Mony J.; Wisniewski, Thomas; Pavlov, Evgeny; Fossati, Silvia.

In: Aging Cell, Vol. 17, No. 4, e12787, 01.08.2018.

Research output: Contribution to journalArticle

Solesio, ME, Peixoto, PM, Debure, L, Madamba, SM, de Leon, MJ, Wisniewski, T, Pavlov, E & Fossati, S 2018, 'Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity', Aging Cell, vol. 17, no. 4, e12787. https://doi.org/10.1111/acel.12787
Solesio ME, Peixoto PM, Debure L, Madamba SM, de Leon MJ, Wisniewski T et al. Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. Aging Cell. 2018 Aug 1;17(4). e12787. https://doi.org/10.1111/acel.12787
Solesio, María E. ; Peixoto, Pablo M. ; Debure, Ludovic ; Madamba, Stephen M. ; de Leon, Mony J. ; Wisniewski, Thomas ; Pavlov, Evgeny ; Fossati, Silvia. / Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. In: Aging Cell. 2018 ; Vol. 17, No. 4.
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