title: Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence.
abstract: The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer's disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer's disease.
authors.affiliation: Department of Pharmacology, Center for Translational Medicine Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Center for Translational Medicine Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Center for Translational Medicine Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: Department of Biochemistry, Center for Translational Medicine Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Stough
authors.affiliation: Department of Biochemistry, Center for Translational Medicine Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: Department of Pharmacology, Center for Translational Medicine Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D019076:Transgenes
chemical_list: D016229:Amyloid beta-Peptides; D016859:Lipoxygenase Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; C552288:gamma-secretase activating protein, mouse; D001094:Arachidonate 5-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases; C505409:Casp3 protein, mouse; D053148:Caspase 3