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

Abstract

IntroductionCerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies.MethodsBased 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.ResultsBoth 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.DiscussionThis work substantiates the potential application of CAIs in clinical trials for AD and CAA.

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

“…More recently, an overexpression of the mitochondrial isoform CA VB was reported in human post mortem brain samples from AD patients presenting cerebral amyloid angiopathy. Such an increase was also reported in the brains of TgSWDI mice, a well-known transgenic AD model Figure ) and methazolamide ( MTZ , Figure ), prevented amyloid-β peptide (Aβ)-mediated apoptosis in neuronal, brain microvascular endothelial, and vascular smooth muscle cells by impeding different mitochondria-mediated proapoptotic mechanisms, such as CytC release, loss of the mitochondrial membrane potential, and production of mitochondrial ROS. − The same compounds protected against cerebrovascular pathology and cognitive impairments observed TgSWDI mice.…”

“…Indeed, chronic treatment with CAIs reduced Aβ burden in neuronal, vascular, and glial cells, decreased Aβ-driven caspase-3 activation in endothelial cells in microglia, astrocytes, and endothelial and smooth muscle cells, and prevented glial overactivation. These inhibitors also showed important effects on modulating cerebral blood flow, alleviating microvessel constriction, and reducing microhemorrhages. ,, All of these mechanisms suggest potential effectiveness for AD therapy. However, no study accessed the effects of CAIs on clinics.…”

“…Such an increase was also reported in the brains of TgSWDI mice, a well-known transgenic AD model. 33 In vitro, it was shown that two FDA-approved classical CA inhibitors (CAIs), acetazolamide (AAZ, Figure 1) and methazolamide (MTZ, Figure 1), prevented amyloid-β peptide (Aβ)-mediated apoptosis in neuronal, brain microvascular endothelial, and vascular smooth muscle cells by impeding different mitochondria-mediated proapoptotic mechanisms, such as CytC release, loss of the mitochondrial membrane potential, and production of mitochondrial ROS. 34−36 The same compounds protected against cerebrovascular pathology and cognitive impairments observed TgSWDI mice.…”

“…These inhibitors also showed important effects on modulating cerebral blood flow, alleviating microvessel constriction, and reducing microhemorrhages. 33,34,36 All of these mechanisms suggest potential effectiveness for AD therapy. However, no study accessed the effects of CAIs on clinics.…”

Synthesis of Novel Hydrazide–Hydrazone Compounds and In Vitro and In Silico Investigation of Their Biological Activities against AChE, BChE, and hCA I and II

“…24 Together with the well-known roles of AChE and butyrylcholinesterase (BChE) enzymes at the AD, it has also been shown that CA inhibitors reduce amyloid β pathology and improve cognition by ameliorating cerebrovascular health and glial fitness. 25 Studies have demonstrated that CA inhibitors such as acetazolamide (AZA) and methazolamide (MTZ) mitigate mitochondrial dysfunction and apoptosis triggered by amyloid β in both vascular and neural cells. This effect is achieved by diminishing the production of reactive oxygen species (ROS) within the mitochondria and preventing the decline of mitochondrial membrane potential.…”