Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-β in amplifying neuronal damage in Alzheimer's disease: Three partners in crime

Paola Gamba, Gabriella Leonarduzzi, Elena Tamagno, Michela Guglielmotto, Gabriella Testa, Barbara Sottero, Simona Gargiulo, Fiorella Biasi, Alessandro Mauro, José Viña, Giuseppe Poli

Research output: Contribution to journalArticle

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 Aβ1-42 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 (1μm) depends on its strong enhancement of the intracellular generation of NADPH oxidase-dependent reactive oxygen species (ROS), mainly H2O2, 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.

Original languageEnglish
Pages (from-to)403-417
Number of pages15
JournalAging Cell
Volume10
Issue number3
DOIs
Publication statusPublished - Jun 2011

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Cholesterol
  • Neurotoxicity
  • Oxidative stress
  • Oxysterols

ASJC Scopus subject areas

  • Cell Biology
  • Ageing

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    Gamba, P., Leonarduzzi, G., Tamagno, E., Guglielmotto, M., Testa, G., Sottero, B., Gargiulo, S., Biasi, F., Mauro, A., Viña, J., & Poli, G. (2011). Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-β in amplifying neuronal damage in Alzheimer's disease: Three partners in crime. Aging Cell, 10(3), 403-417. https://doi.org/10.1111/j.1474-9726.2011.00681.x