期刊
NEUROBIOLOGY OF AGING
卷 21, 期 2, 页码 183-197出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S0197-4580(99)00111-6
关键词
Alzheimer's disease; beta-amyloid-induced vasoactivity; phospholipase A(2); cyclooxygenase; lipoxygenase; p38 MAPK; p42/44 MAPK; arachidonic acid; inflammation; cerebrovasculature; prostaglandin; soluble beta-amyloid; transgenic mice
Freshly solubilized beta-amyloid (A beta) peptides display vasoactive properties, increasing both the magnitude and the duration of endothelin-1-induced vasoconstriction. We show that A beta vasoactivity is mediated by the stimulation of a pro-inflammatory pathway involving activation of secretory phospholipase 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 eicosanoids via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of which we show to be required for A beta vasoactivity. Accordingly, p38 MAPK activity is higher in the brains of transgenic mice that overproduce A beta, and COX-2 immunoreactivity is increased in the cerebrovasculature of these transgenic animals. Taken together, our data show that freshly solubilized A beta 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. (C) 2000 Elsevier Science Inc. All rights reserved.
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