Aβ Vasoactivity: An Inflammatory Reaction

A bstract : Mounting evidence from in vitro and in vivo studies in transgenic mice overproducing β‐amyloid peptides (Aβ) suggests that Aβ can induce vasoconstriction and decrease cerebral blood flow. In this report, we describe the vasoactive properties of Aβ, in particular the enhancement of endothelin‐1‐induced vasoconstriction and Aβ's induction of a long‐lasting vasoconstrictive event. Furthermore, we show that low doses (as low as 50 nM) of freshly solubilized Aβ similar to those observed in the plasma of patients suffering from Alzheimer's disease are vasoactive. By using various inhibitors and activators of the phospholipase A 2 (PLA 2 )/arachidonic acid (AA) cascade, we demonstrate that Aβ vasoactivity is dependent on activation of this intracellular signaling pathway, resulting in stimulation of downstream cyclooxygenase‐2 and 5‐lipoxygenase, which mediate production of proinflammatory eicosanoids. Taken together, our data show that Aβ directly activates an intracellular proinflammatory pathway, which is responsible for its vasoactive properties.