It has recently been shown that the level of soluble β-amyloid (Aβ) peptides correlates well with the severity of synaptic loss and the density of neurofibrillary tangles observed in Alzheimer's disease (AD) brain. However, the biological activity of soluble forms of Aβ peptides in the brain remains to be determined. We have investigated ex vivo the effect of freshly solubilized Aβ 1 - 4 0 peptides (fsAβ) on prostaglandin E 2 (PGE 2 ) production in rat brain slices. PGE 2 levels increased rapidly following treatment with fsAβ, an effect that was prevented by SB202190, a selective inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), and by NS-398, which preferentially inhibits cyclooxygenase-2 (COX-2) compared to COX-1. In an attempt to determine the cellular systems of the brain responsible for prostaglandin production in response to fsAβ, the effect of fsAβ was tested on isolated brain microvessels, primary cultures of brain smooth muscle cells/pericytes and endothelial cells, and a human neuron-like cell line (IMR32). Our data show that fsAβ ex vivo can stimulate prostaglandin accumulation in incubates of isolated rat brain microvessels. In addition, fsAβ appears to cause a concentration-dependent enhancement of prostaglandin accumulation in primary cultures of brain microvessel-derived smooth muscle cells/pericytes but not of brain endothelial cells. Finally, fsAβ also stimulated PGF 2 α accumulation in cultures of differentiated IMR32 cells, but to a lesser extent than in brain smooth muscle cell/pericyte cultures. Deposition of aggregated forms of Aβ in the brain has been thought to trigger an inflammatory response which accompanies the neuropathologic events of AD. Our data provide evidence that fsAβ triggers a pro-inflammatory reaction in rat brain, and suggest that the cerebrovasculature may constitute an important source of pro-inflammatory eicosanoids.