title: A protective role for lipid raft cholesterol against amyloid-induced membrane damage in human neuroblastoma cells.
abstract: Increasing evidence supports the idea that the initial events of Abeta oligomerization and cytotoxicity in Alzheimer's disease involve the interaction of amyloid Abeta-derived diffusible ligands (ADDLs) with the cell membrane. This also indicates lipid rafts, ordered membrane microdomains enriched in cholesterol, sphingolipids and gangliosides, as likely primary interaction sites of ADDLs. To shed further light on the relation between ADDL-cell membrane interaction and oligomer cytotoxicity, we investigated the dependence of ADDLs binding to lipid rafts on membrane cholesterol content in human SH-SY5Y neuroblastoma cells. Confocal laser microscopy showed that Abeta1-42 oligomers markedly interact with membrane rafts and that a moderate enrichment of membrane cholesterol prevents their association with the monosialoganglioside GM1. Moreover, anisotropy fluorescence measurements of flotillin-1-positive rafts purified by sucrose density gradient suggested that the content of membrane cholesterol and membrane perturbation by ADDLs are inversely correlated. Finally, contact mode atomic force microscope images of lipid rafts in liquid showed that ADDLs induce changes in raft morphology with the appearance of large cavities whose size and depth were significantly reduced in similarly treated cholesterol-enriched rafts. Our data suggest that cholesterol reduces amyloid-induced membrane modifications at the lipid raft level by altering raft physicochemical features.
authors: Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy. cristina.cecchi@unifi.it
authors: Cristina
authors: C
authors: Cecchi
authors: Daniela
authors: D
authors: Nichino
authors: Mariagioia
authors: M
authors: Zampagni
authors: Caterina
authors: C
authors: Bernacchioni
authors: Elisa
authors: E
authors: Evangelisti
authors: Anna
authors: A
authors: Pensalfini
authors: Gianfranco
authors: G
authors: Liguri
authors: Alessandra
authors: A
authors: Gliozzi
authors: Massimo
authors: M
authors: Stefani
authors: Annalisa
authors: A
authors: Relini
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000502:physiology*; D006801:Humans; D021962:Membrane Microdomains / Q000502:physiology*; D018625:Microscopy, Atomic Force; D009447:Neuroblastoma / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D002784:Cholesterol