Statins inhibit Aβ-neurotoxicity in vitro and Aβ-induced vasoconstriction and inflammation in rat aortae

Abstract

Freshly solubilized Aβ peptides synergistically increase the magnitude of the constriction induced by endothelin-1 (ET-1), via the activation of a pro-inflammatory pathway. We report that mevinolin and mevastatin, two inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are able to completely abolish the vasoactive properties of Aβ in rat aortae. Mevinolin also appears to oppose the increased vascular reactivity to ET-1 induced by interleukin 1-β and phospholipase A 2 suggesting that statins display some anti-inflammatory properties. We show that freshly solubilized Aβ stimulates prostaglandin E 2 and F 2α production (by 6 and 3.6 times, respectively) in isolated rat aortae and that mevinolin completely antagonizes this effect confirming the anti-inflammatory action of mevinolin ex vivo in rat aortae. In addition, we observed that Aβ vasoactivity is not mediated nor modulated by mevalonic acid suggesting that the anti-inflammatory action of the statins are not related to an inhibition of HMG-CoA reductase activity. Differentiated human neuroblastoma cells (IMR32) were used to assess the neurotoxic effect of pre-aggregated Aβ by quantifying the release of lactate dehydrogenase (LDH) in the cell culture medium. Aβ appears to enhance LDH release by 30% in IMR32 cells, an effect that can be completely opposed by mevastatin. Taken together these data show that statins can antagonize the effect of Aβ in different assays and provide new clues to understand the prophylactic action of the statins against Alzheimer's disease.