title: Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α 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 APPα (sAPPα). 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 δ (PPARδ) in human brain microvascular endothelial cells. PPARδ-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARδ) upregulated ADAM10 and increased production of sAPPα. Genetic deletion of endothelial PPARδ (ePPARδ-/-) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPα. In vivo treatment with GW501516 increased sAPPα content in hippocampus of wild type mice but not in hippocampus of ePPARδ-/-mice. Our findings identified previously unrecognized role of IP-PPARδ signal transduction pathway in the production of sAPPα in cerebral microvasculature.
authors.affiliation: Department of Anesthesiology and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Tongrong
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Anesthesiology and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Anantha Vijay R
authors.initials: AV
authors.lastname: Santhanam
authors.affiliation: Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Livius V
authors.initials: LV
authors.lastname: d'Uscio
authors.affiliation: Department of Anesthesiology and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA katusic.zvonimir@mayo.edu.
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000098:blood supply*; D004730:Endothelium, Vascular / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility
chemical_list: D047495:PPAR gamma; C113936:PTGIR protein, human; D044006:Receptors, Epoprostenol; D011464:Epoprostenol; D053829:Amyloid Precursor Protein Secretases
keywords: ADAM10; APP; PPARδ; endothelium; sAPPα