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

Freshly solubilized beta-amyloid (A beta) peptides display vasoactive prope rties, increasing both the magnitude and the duration of endothelin-1-induc ed vasoconstriction. We show that A beta vasoactivity is mediated by the st imulation of a pro-inflammatory pathway involving activation of secretory p hospholipase A(2) (PLA(2)), mitogen activated protein kinase (MAPK) kinase (MEK1/2), p38 MAPK, cytosolic PLA(2), and the release of arachidonic acid. Ultimately, arachidonic acid is metabolized into proinflammatory eicosanoid s via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of whic h we show to be required for A beta vasoactivity. Accordingly, p38 MAPK act ivity is higher in the brains of transgenic mice that overproduce A beta, a nd COX-2 immunoreactivity is increased in the cerebrovasculature of these t ransgenic animals. Taken together, our data show that freshly solubilized A beta peptides can trigger a pro-inflammatory reaction in the vasculature t hat can be blocked by inhibiting specific target molecules, providing the b asis for novel therapeutic intervention. (C) 2000 Elsevier Science Inc. All rights reserved.