Mounting evidence from
in vitro and
in vivo studies in transgenic
mice overproducing ß-amyloid peptides (Aß)
suggests that Aß can induce vasoconstriction and decrease
cerebral blood flow. In this report, we describe the vasoactive
properties of Aß, in particular the enhancement of
endothelin-1-induced vasoconstriction and Aß's induction
of a long-lasting vasoconstrictive event. Furthermore, we show
that low doses (as low as 50 nM) of freshly solubilized Aß
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 Aß 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 Aß
directly activates an intracellular proinflammatory pathway,
which is responsible for its vasoactive properties.
