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

ABSTRACT: We tested hypothesis that activation of the prostacyclin (PGI₂) 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 PGI₂, 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? (sAPP?). 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 ? (PPAR?) in human brain microvascular endothelial cells. PPAR?-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPAR?) upregulated ADAM10 and increased production of sAPP?. Genetic deletion of endothelial PPAR? (ePPAR?^-/-) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPP?. In vivo treatment with GW501516 increased sAPP? content in hippocampus of wild type mice but not in hippocampus of ePPAR?^-/- mice. Our findings identified previously unrecognized role of IP-PPAR? signal transduction pathway in the production of sAPP? in cerebral microvasculature.

SUBMITTER: He T 

PROVIDER: S-EPMC5363732 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature