FDA-approved carbonic anhydrase inhibitors reduce amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness

Elisa Canepa, Rebecca Parodi-Rullan, Rafael Vazquez-Torres, Begona Gamallo-Lana, Roberto Guzman-Hernandez, Nicole L Lemon, Federica Angiulli, Ludovic Debure, Marc A Ilies, Leif Østergaard, Thomas Wisniewski, Eugenio Gutiérrez-Jiménez, Adam C Mar, Silvia Fossati*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

INTRODUCTION: Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies.

METHODS: Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness.

RESULTS: Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA-VB silencing specifically reduces Aβ-mediated endothelial apoptosis.

DISCUSSION: This work substantiates the potential application of CAIs in clinical trials for AD and CAA.

Original languageEnglish
JournalAlzheimer's & Dementia
Volume19
Issue11
Pages (from-to)5048-5073
Number of pages26
ISSN1552-5260
DOIs
Publication statusPublished - Nov 2023

Keywords

  • United States
  • Humans
  • Mice
  • Animals
  • Amyloid beta-Peptides/metabolism
  • Carbonic Anhydrase Inhibitors/pharmacology
  • Endothelial Cells/metabolism
  • Cerebral Amyloid Angiopathy/drug therapy
  • Alzheimer Disease/pathology
  • Cognition

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