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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. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular (CV) risk factors may potentiate cerebral amyloid angiopathy (CAA) pathology and neurovascular dysfunction, worsening neurodegeneration. The role of the mitochondria, key regulators of cell survival and death, in mediating cerebral endothelial cell (EC) dysfunction during CAA complicated with CV risk factors is unknown. Our lab has demonstrated that carbonic anhydrase inhibitors (CAi) reduce amyloid‐induced cell death and mitochondrial dysfunction in EC. Here, we aim to understand the role of the mitochondria in the pathogenesis of mixed AD and vascular dementias. Furthermore, we seek to understand the effects of pan‐CAi and CAi with high selectivity for mitochondria‐localized isoforms (mCAi) in preventing the toxic effects of amyloid β (Aβ) and hyperhomocysteinemia (HHcy). Methods: Human ECs were challenged with Aβ, Hcy, or the combination in the presence or absence of CAi. Cell death, mitochondrial function, and blood‐brain barrier (BBB) resistance effects were evaluated. Results: The presence of Aβ and/or HHcy induced EC apoptosis, mediated by death receptors activation and mitochondrial dysfunction, and attenuated by CAi and mCAi. BBB permeability was increased by both Aβ and HHcy, and HHcy worsened amyloid‐induced barrier permeability. These effects were prevented by CAi and mCAi. Conclusion: Both HHcy and Aβ had detrimental effects on EC mitochondrial function and BBB permeability, and HHcy worsened the effects of Aβ. These effects were prevented by CAi and mCAi. The ability of mCAi to protect against Aβ and/or HHcy suggests a central role of the mitochondria in mediating vascular dysfunction in the presence of Aβ and/or HHcy. Our studies support the importance of better understanding mitochondrial and EC pathways responsible for cerebrovascular dysfunction in CAA and mixed dementias. [ABSTRACT FROM AUTHOR]

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)