title: Lipid rafts are primary mediators of amyloid oxidative attack on plasma membrane.
abstract: Increasing evidence indicates that cell surfaces are early interaction sites for Abeta-derived diffusible ligands (ADDLs) and neurons in Alzheimer's disease (AD) pathogenesis. Our previous data showed significant oxidative damage at the plasma membrane in fibroblasts from familial AD patients with enhanced Abeta production. Here, we report that lipid rafts, ordered membrane microdomains, are chronic mediators of Abeta-induced lipid peroxidation in SH-SY5Y human neuroblastoma cells overexpressing amyloid precursor protein (APPwt) and APPV717G genes and in fibroblasts bearing the APPV717I gene mutation. Confocal microscope analysis showed that Abeta-oxidised rafts recruit more ADDLs than corresponding domains in control cells, triggering a further increase in membrane lipid peroxidation and loss of membrane integrity. Moreover, amyloid pickup at the oxidative-damaged domains was prevented by enhanced cholesterol levels, anti-ganglioside (GM1) antibodies, the B subunit of cholera toxin and lipid raft structure alteration. An enhanced structural rigidity of the detergent-resistant domains, isolated from APPwt and APPV717G cells and exposed to ADDLs, indicates a specific perturbation of raft physicochemical features in cells facing increased amyloid assembly at the membrane surface. These data identify lipid rafts as key mediators of oxidative damage as a result of their ability to recruit aggregates to the cell surface.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
authors.forename: Mariagioia
authors.initials: M
authors.lastname: Zampagni
authors.forename: Elisa
authors.initials: E
authors.lastname: Evangelisti
authors.forename: Roberta
authors.initials: R
authors.lastname: Cascella
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Liguri
authors.forename: Matteo
authors.initials: M
authors.lastname: Becatti
authors.forename: Anna
authors.initials: A
authors.lastname: Pensalfini
authors.forename: Daniela
authors.initials: D
authors.lastname: Uberti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Memo
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagnoli
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.forename: Cristina
authors.initials: C
authors.lastname: Cecchi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D015227:Lipid Peroxidation; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002784:Cholesterol