title: Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice.
abstract: The enzyme 5-lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD), and its pharmacologic blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12 months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid, and tau pathology assessed. Although mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significantly less Aβ deposits and tau phosphorylation secondary to reduced γ-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease.
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Antonio
authors: A
authors: Di Meco
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Elisabetta
authors: E
authors: Lauretti
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Alana N
authors: AN
authors: Vagnozzi
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA. Electronic address: praticod@temple.edu.
authors: Domenico
authors: D
authors: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008568:Memory; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000201:enzymology* / Q000523:psychology; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D058227:Amyloidogenic Proteins; D016859:Lipoxygenase Inhibitors; D066329:Protein Aggregates; D016875:tau Proteins; D001094:Arachidonate 5-Lipoxygenase; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D053829:Amyloid Precursor Protein Secretases; C063449:zileuton; D006918:Hydroxyurea
keywords: 5-Lipoxygenase; Alzheimer's disease; Amyloid beta; Memory; Tau protein; Transgenic mouse models