P3‐464: CARBONIC ANHYDRASE INHIBITORS AMELIORATE NEUROVASCULAR DYSFUNCTION IN A MOUSE MODEL OF CEREBRAL AMYLOID ANGIOPATHY

Abstract

Neurodegeneration and memory loss in Alzheimer's disease (AD) have been associated with both vascular and mitochondrial dysfunction. Our studies and others pointed to mitochondrial deregulation, production of reactive oxygen species and release of pro-apoptotic factors from the mitochondria, as early events in the neurovascular pathogenesis of cerebral amyloid angiopathy (CAA) and AD. Carbonic anhydrase inhibitors (CAIs) are clinically used for the treatment of glaucoma and for the prevention of high altitude sickness and related cerebral edema. We were the first to demonstrate that these compounds inhibit Amyloid beta-mediated release of cytochrome C and H2O2 from the mitochondria. Here we aimed to clarify the protective effects of CAIs methazolamide and acetazolamide against mitochondrial dysfunction in vitro and in vivo and their effects in ameliorating neurovascular pathology in animal models of CAA. We tested the effects of Aβ, in presence or absence of the drugs, on mitochondrial membrane potential, calcium influx, production of hydrogen peroxide and ATP, cellular pH, and caspase activation. MTZ and analogs prevented activation of caspases and apoptotic cell death induced by Aβ in both vascular and neuronal cells through the inhibition of mitochondrial hydrogen peroxide production and the loss of mitochondrial membrane potential. The drugs also proved to be effective in animal models of CAA (TgSwDI mice), reducing brain caspase 3 activation, neurovascular pathology, inflammation and neurodegeneration in the mice. Based on our results, CAIs inhibit specific mitochondrial stress and cell death pathways in models of CAA, and may represent a new repurposed therapeutic strategy against neurovascular degeneration in AD.