title: A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease.
abstract: Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging - the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This paper reports that, in human neuronal cells, oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system leads to apoptotic cell death. Microarray analyses showed a potent activation of the cholesterol biosynthesis pathway following reductions in the cell cholesterol synthesis caused by the X-XOD treatment; furthermore, the apoptosis was reduced by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) expression with an interfering RNA. The potential importance of this mechanism in AD was investigated by genetic association, and it was found that HMGCR, a key gene in cholesterol metabolism and among those most strongly upregulated, was associated with AD risk. In summary, this work presents a human cell model prepared to mimic the effect of oxidative stress in neurons that might be useful in clarifying the mechanism involved in free radical-induced neurodegeneration. Gene expression analysis followed by genetic association studies indicates a possible link among oxidative stress, cholesterol metabolism and AD.
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Cantoblanco, 28049 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Recuero
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Vicente
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-García
authors.forename: María C
authors.initials: MC
authors.lastname: Ramos
authors.forename: Pedro
authors.initials: P
authors.lastname: Carmona-Saez
authors.forename: Isabel
authors.initials: I
authors.lastname: Sastre
authors.forename: Jesús
authors.initials: J
authors.lastname: Aldudo
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.forename: Ana
authors.initials: A
authors.lastname: Frank
authors.forename: María J
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Fernando
authors.initials: F
authors.lastname: Valdivieso
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D001923:Brain Chemistry / Q000502:physiology*; D002784:Cholesterol / Q000096:biosynthesis*; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology*; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism
chemical_list: D005609:Free Radicals; D019820:Xanthine; D002784:Cholesterol; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D014969:Xanthine Oxidase