title: Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease.
abstract: The accumulation of intracellular β amyloid (Aβ) may be one of the factors leading to neuronal cell death in Alzheimer's disease (AD). Using a pyrazole called CNB-001, which was selected for its ability to reduce intracellular Aβ, we show that the activation of the eIF2α/ATF4 arm of the unfolded protein response is sufficient to degrade aggregated intracellular Aβ. CNB-001 is a potent inhibitor of 5-lipoxygenase (5-LOX), decreases 5-LOX expression, and increases proteasome activity. 5-LOX inhibition induces eIF2α and PERK (protein kinase R-like extracellular signal-regulated kinase) phosphorylation, and HSP90 and ATF4 levels. When fed to AD transgenic mice, CNB-001 also increases eIF2α phosphorylation and HSP90 and ATF4 levels, and limits the accumulation of soluble Aβ and ubiquitinated aggregated proteins. Finally, CNB-001 maintains the expression of synapse-associated proteins and improves memory. Therefore, 5-LOX metabolism is a key element in the promotion of endoplasmic reticulum dysfunction, and its inhibition under conditions of stress is sufficient to reduce proteotoxicity both in vivo and in vitro.
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, California 92037-1002, USA.
authors.forename: Elvira
authors.initials: E
authors.lastname: Valera
authors.forename: Richard
authors.initials: R
authors.lastname: Dargusch
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Maher
authors.forename: David
authors.initials: D
authors.lastname: Schubert
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D017510:Protein Folding; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C081452:Atf4 protein, mouse; C529348:CNB 001; D018491:Dopamine Agonists; D015852:Eukaryotic Initiation Factor-2; D016859:Lipoxygenase Inhibitors; D010446:Peptide Fragments; D011720:Pyrazoles; D012333:RNA, Messenger; D025801:Ubiquitin; C075222:amyloid beta-protein (1-42); D051701:Activating Transcription Factor 4; D001094:Arachidonate 5-Lipoxygenase; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin; D001058:Apomorphine