Interaction between 24‐hydroxycholesterol, oxidative stress, and amyloid‐β in amplifying neuronal damage in Alzheimer’s disease: three partners in crime

Aging Cell

Paola Gamba⁴  Gabriella Leonarduzzi⁴  Elena Tamagno³  Michela Guglielmotto³  Gabriella Testa⁴  Barbara Sottero⁴  Simona Gargiulo⁴  Fiorella Biasi⁴  Alessandro Mauro²  José Viña¹ 

[1] Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain;Division of Neurology and Neurorehabilitation, IRCCS Istituto Auxologico Italiano, Verbania, Italy and Department of Neurosciences, University of Turin, Turin, Italy;Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy;Department of Clinical and Biological Sciences, Faculty of Medicine San Luigi Gonzaga, University of Turin, Turin, Italy

关键词: cholesterol;    Alzheimer’s disease;    oxysterols;    amyloid‐β;    oxidative stress;    neurotoxicity;   

DOI  :  10.1111/j.1474-9726.2011.00681.x

来源: Wiley

【 摘 要 】

Summary

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 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.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland