Membrane cholesterol interferes with neuronal apoptosis induced by soluble oligomers but not fibrils of amyloid-beta peptide.
Neuronal cell death in Alzheimer's disease (AD) is partly induced by the interaction of the amyloid-beta peptide (Abeta) with the plasma membrane of target cells. Accordingly, recent studies have suggested that cholesterol, an important component of membranes that controls their physical properties and functions, plays a critical role in neurodegenerative diseases. We report here that the enrichment of the neuronal plasma membrane with cholesterol protects cortical neurons from apoptosis induced by soluble oligomers of the Abeta(1-40) peptide. Conversely, cholesterol depletion using cyclodextrin renders cells more vulnerable to the cytotoxic effects of the Abeta-soluble oligomers. Increasing the cholesterol content of small unilamellar liposomes also decreases Abeta-dependent liposome fusion. We clearly demonstrate that cholesterol protection is specific to the soluble conformation of Abeta, because we observed no protective effects on cortical neurons treated by amyloid fibrils of the Abeta(1-40) peptide. This may provide a new opportunity for the development of an effective AD therapy as well as elucidate the impact of the cholesterol level during AD development.
Sponne
Isabelle
I
INSERM EMI 0014, Université de Nancy I, Vandoeuvre, France.
Fifre
Alexandre
A
Koziel
Violette
V
Oster
Thierry
T
Olivier
Jean-Luc
JL
Pillot
Thierry
T
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001704:Biopolymers; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D002784:Cholesterol / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D008051:Lipid Bilayers; D008081:Liposomes; D008560:Membrane Fluidity; D008561:Membrane Fusion / Q000187:drug effects; D008563:Membrane Lipids / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D008051:Lipid Bilayers; D008081:Liposomes; D008563:Membrane Lipids; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C419409:amyloid beta-protein (29-40); D002784:Cholesterol; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases