Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

We tested hypothesis that activation of the prostacyclin (PGI(2)) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI(2), iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APP alpha (sAPP alpha). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor delta (PPAR delta) in human brain microvascular endothelial cells. PPAR delta-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPAR delta) upregulated ADAM10 and increased production of sAPP alpha. Genetic deletion of endothelial PPAR delta (ePPAR delta(-/-)) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPP alpha. In vivo treatment with GW501516 increased sAPP alpha content in hippocampus of wild type mice but not in hippocampus of ePPAR delta(-/-) mice. Our findings identified previously unrecognized role of IP-PPAR delta signal transduction pathway in the production of sAPP alpha in cerebral microvasculature.