Inhibition of mitochondrial carbonic anhydrases reduces Amyloid β induced cell death in cerebral endothelial cells

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS) which has been observed to become dysfunctional in Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA). Cerebrovascular amyloid disrupts the function of brain endothelial cells (ECs). Previous findings from our lab demonstrated that Acetazolamide (ATZ) and methazolamide (MTZ), both pan‐carbonic anhydrase (CA) inhibitors, prevent NVU cell death in models of AD and CAA. Although these FDA‐approved pan‐CA inhibitors are protective, a more specific targeting of the isoforms involved in AD pathology may not only reduce side effects, but also increase the efficacy of pan‐CA inhibition. We have shown that CAIs reduce Aβ‐induced cytochrome C release from the mitochondria, caspase‐9 activation, and mitochondrial H2O2 production in NVU cells. Therefore, we hypothesize that mitochondrial CA‐VA/B are the main isoforms involved in these mechanisms and we anticipate that using inhibitors selective for CA‐VA/B will prevent cerebral EC apoptosis, thereby reducing NVU dysfunction and AD progression.