Soluble β-amyloid peptides mediate vasoactivity via activation of a pro-inflammatory pathway

Freshly solubilized β-amyloid (Aβ) peptides display vasoactive properties, increasing both the magnitude and the duration of endothelin-1-induced vasoconstriction. We show that Aβ vasoactivity is mediated by the stimulation of a pro-inflammatory pathway involving activation of secretory phospholipase A2 (PLA2), mitogen activated protein kinase (MAPK) kinase (MEK1/2), p38 MAPK, cytosolic PLA2, and the release of arachidonic acid. Ultimately, arachidonic acid is metabolized into proinflammatory eicosanoids via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of which we show to be required for Aβ vasoactivity. Accordingly, p38 MAPK activity is higher in the brains of transgenic mice that overproduce Aβ, and COX-2 immunoreactivity is increased in the cerebrovasculature of these transgenic animals. Taken together, our data show that freshly solubilized Aβ peptides can trigger a pro-inflammatory reaction in the vasculature that can be blocked by inhibiting specific target molecules, providing the basis for novel therapeutic intervention.