title: Five lipoxygenase hypomethylation mediates the homocysteine effect on Alzheimer's phenotype.
abstract: Environmental and genetic risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). However, how they interact and influence its pathogenesis remains to be investigated. High level of homocysteine (Hcy) is an AD risk factor and associates with an up-regulation of the ALOX5 gene. In the current paper we investigated whether this activation is responsible for the Hcy effect on the AD phenotype and the mechanisms involved. Triple transgenic mice were randomized to receive regular chow diet, a diet deficient in folate and B vitamins (Diet), which results in high Hcy, or the Diet plus zileuton, a specific ALOX5 inhibitor, for 7 months. Compared with controls, Diet-fed mice had a significant increase in Hcy levels, memory and learning deficits, up-regulation of the ALOX5 pathway, increased Aβ levels, tau phosphorylation, and synaptic pathology, which were absent in mice treated with zileuton. In vivo and vitro studies demonstrated that the mechanism responsible was the hypomethylation of the ALOX5 promoter. Our findings demonstrate that the up-regulation of the ALOX5 is responsible for the Hcy-dependent worsening of the AD phenotype in a relevant mouse model of the disease. The discovery of this previously unknown cross-talk between these two pathways could afford novel therapeutic opportunities for treating or halting AD.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Temple University Philadelphia, PA 19140, USA.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, Temple University Philadelphia, PA 19140, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Barrero
authors.affiliation: Department of Pharmaceutical Sciences, Temple University Philadelphia, PA 19140, USA.
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Temple University Philadelphia, PA 19140, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D019175:DNA Methylation / Q000187:drug effects; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000150:complications / Q000473:pathology; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D008084:Lipoxygenase / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014803:Vitamin B Complex / Q000378:metabolism; D014804:Vitamin B Deficiency / Q000150:complications / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid; D008084:Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea