Membrane cholesterol content plays a key role in the neurotoxicity of β‐amyloid: implications for Alzheimer’s disease

Aging Cell

Andrey Y. Abramov¹  Maksim Ionov³  Evgeny Pavlov² 

[1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada;Department of General Biophysics, University of Lodz, Banacha st. 12/16, Lodz 90-237, Poland

关键词: astrocyte;    calcium;    cholesterol;    neurodegeneration;    neuron;    β‐amyloid;   

DOI  :  10.1111/j.1474-9726.2011.00685.x

来源: Wiley

【 摘 要 】

Summary

Beta amyloid (βA) plays a central role in the pathogenesis of the most common and devastating neurodegenerative disorder, Alzheimer’s disease (AD). The mechanisms of βA neurotoxicity remain controversial, but include dysregulation of calcium homeostasis and oxidative stress. A large body of data suggest that cholesterol plays a significant role in AD. In mixed cultures containing hippocampal neurons and astrocytes, we have shown that neurotoxic βA peptides (1–42 and 25–35) cause sporadic cytosolic calcium ([Ca²⁺]_c) signals in astrocytes but not in neurons, initiating a cascade that ends in neuronal death. We now show, using the cholesterol-sensitive fluorescent probe, Filipin, that membrane cholesterol is significantly higher in astrocytes than in neurons and mediates the selective response of astrocytes to βA. Thus, lowering [cholesterol] using mevastatin, methyl-β-cyclodextrin or filipin prevented the βA-induced [Ca²⁺]_c signals, while increased membrane [cholesterol] increased βA-induced [Ca²⁺]_c signals in both neurons and astrocytes. Addition of βA to lipid bilayers caused the appearance of a conductance that was significantly higher in membranes containing cholesterol. Increasing membrane [cholesterol] significantly increased βA-induced neuronal and astrocytic death. We conclude that a high membrane [cholesterol] promotes βA incorporation into membranes and increased [Ca²⁺]_c leading to cell death.

【 授权许可】

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