Mitochondrial carbonic anhydrase–VB inhibition rescues brain endothelial stress and memory in Alzheimer’s disease models

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) 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 Aβ 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.