title: Modulation of amyloid-β production by leukotriene B4 via the γ-secretase pathway.
abstract: Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) pathogenesis, and among them, the pro-inflammatory 5-lipoxygenase (5LO) enzyme. While previous work has shown that 5LO modulates the amyloidotic phenotype of AD, the exact metabolic product responsible for this biological action remains unknown. In this study, we challenged neuronal cells with leukotriene B4 (LTB4), a major 5LO product, and found that it increased amyloid-β formation whereby elevating the steady-state levels of the γ-secretase proteins, suggesting that LTB4 is the mediator of the 5LO effect. Therapies that by blocking 5LO activation suppress the formation of LTB4 or its action represent novel AD therapeutic opportunities.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Yash B
authors.initials: YB
authors.lastname: Joshi
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Meco
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticó
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C469349:PSENEN protein, human; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C413604:nicastrin protein; D007975:Leukotriene B4; D053829:Amyloid Precursor Protein Secretases
keywords: 5-lipoxygenase; Alzheimer's disease; amyloid-β; leukotriene B$_4$; γ-secretase