Lemon, N. L. | Search bioRxiv

bioRxiv2026

Mitochondrial Carbonic Anhydrase-VB inhibition rescues brain endothelial stress and memory in Alzheimer's disease models

Alzheimers Disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated Amyloid-{beta} (A{beta}) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CA) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial CA isoform CA-VB by pharmacological and genetic manipulation, in human cerebral microvascular endothelial cells (hCMEC) and we confirm the protective effects of the CA-V inhibitor in AD mice. CA-V inhibition and CA-VB KO prevent A{beta} induced mitochondria-mediated endothelial apoptosis, loss of barrier resistance, and hCMEC inflammatory activation. Strikingly, CA-V inhibition also mitigates caspase activation and endothelial cell activation in the brains of 3xTg AD mice, resulting in preserved memory function. Our results demonstrate that selective CA-V inhibition is an effective and promising strategy against AD-mediated cerebrovascular pathology, neuroinflammation and cognitive impairment.

neuroscience↗

bioRxiv2022

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

Alzheimers disease (AD) is a devastating neurodegenerative disorder with no effective cure. Cerebrovascular and neurovascular pathology are early and causal hallmarks of AD, where cerebral amyloid angiopathy (CAA), the deposition of amyloid {beta} (A{beta}) at the cerebral vasculature, is present in about 90% of cases. Our previous work has uncovered the protective effect of carbonic anhydrase (CA) inhibition against A{beta}-mediated mitochondrial dysfunction, production of reactive oxygen species (ROS) and apoptosis in vascular, glial and neuronal cells in culture. Here, we tested for the first time in a transgenic model of AD and cerebrovascular amyloidosis, the TgSwDI mice, a therapeutic regimen employing the FDA-approved CA inhibitors (CAIs), methazolamide (MTZ) and acetazolamide (ATZ). These drugs are used in humans for glaucoma, high altitude sickness, and other disorders, and can cross the blood-brain barrier. We found that both CAIs were non- toxic, significantly reduced cerebral amyloidosis, vascular, microglial and astrocytic A{beta} accumulation, and ameliorated cognition. MTZ and ATZ treatment prevented caspase-3 activation in endothelial cells, microglia and astrocytes, reverted capillary constriction and microhemorrhages, reduced gliosis, and induced glial pro-clearance pathways, which are likely responsible for the reduction of A{beta} deposition. Notably, we unveiled a critical new druggable target, revealing that the mitochondrial isozyme CA-VB is specifically upregulated in TgSwDI mouse brains, as well as in human brains of CAA and AD (with CAA) patients. Importantly, A{beta} challenge induced CA-VB overexpression in human cerebral endothelial cells, and CA-VB silencing, mimicking CAIs effects, reduced A{beta}-mediated endothelial apoptosis. This work paves the way for the application of CAIs in clinical trials for AD and CAA and uncovers CA-VB as a mediator of cerebral amyloid toxicity.

neuroscience↗