title: Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-β in amplifying neuronal damage in Alzheimer's disease: three partners in crime.
abstract: All three cholesterol oxidation products implicated thus far in the pathogenesis of Alzheimer's disease, 7β-hydroxycholesterol, 24-hydroxycholesterol, and 27-hydroxycholesterol, markedly enhance the binding of amyloid-beta (Aβ) to human differentiated neuronal cell lines (SK-N-BE and NT-2) by up-regulating net expression and synthesis of CD36 and β1-integrin receptors. However, only 24-hydroxycholesterol markedly potentiates the pro-apoptotic and pro-necrogenic effects of Aβ(1-42) peptide on these cells: 7β-hydroxycholesterol and 27-hydroxycholesterol, like unoxidized cholesterol, show no potentiating effect. This peculiar behavior of 24-hydroxycholesterol at physiologic concentrations (1 μm) depends on its strong enhancement of the intracellular generation of NADPH oxidase-dependent reactive oxygen species (ROS), mainly H(2) O(2) , and the consequent impairment of neuronal cell redox equilibrium, measured in terms of the GSSG/GSH ratio. Cell incubation with antioxidants quercetin or genistein prevents 24-hydroxycholesterol's pro-oxidant effect and potentiation of Aβ-induced necrosis and apoptosis. Thus, the presence of 24-hydroxycholesterol in the close vicinity of amyloid plaques appears to enhance the adhesion of large amounts of Aβ to the plasma membrane of neurons and then to amplify the neurotoxic action of Aβ by locally increasing ROS steady-state levels. This report further supports a primary involvement of altered brain cholesterol metabolism in the complex pathogenesis of Alzheimer's disease.
authors.affiliation: Department of Clinical and Biological Sciences, Faculty of Medicine San Luigi Gonzaga, University of Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gamba
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leonarduzzi
authors.forename: Elena
authors.initials: E
authors.lastname: Tamagno
authors.forename: Michela
authors.initials: M
authors.lastname: Guglielmotto
authors.forename: Gabriella
authors.initials: G
authors.lastname: Testa
authors.forename: Barbara
authors.initials: B
authors.lastname: Sottero
authors.forename: Simona
authors.initials: S
authors.lastname: Gargiulo
authors.forename: Fiorella
authors.initials: F
authors.lastname: Biasi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.forename: José
authors.initials: J
authors.lastname: Viña
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Poli
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019833:Genistein / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D019803:Glutathione Disulfide / Q000032:analysis; D006801:Humans; D006888:Hydroxycholesterols / Q000009:adverse effects* / Q000494:pharmacology; D039641:Integrin beta Chains / Q000096:biosynthesis; D019255:NADPH Oxidases / Q000378:metabolism; D009336:Necrosis / Q000188:drug therapy; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000009:adverse effects*; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D011794:Quercetin / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018955:CD36 Antigens; D006888:Hydroxycholesterols; D039641:Integrin beta Chains; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C044563:24-hydroxycholesterol; C011724:cholest-5-en-3 beta,7 alpha-diol; C076996:27-hydroxycholesterol; D011794:Quercetin; D019833:Genistein; D019255:NADPH Oxidases; D005978:Glutathione; D019803:Glutathione Disulfide