title: Lipid rafts mediate amyloid-induced calcium dyshomeostasis and oxidative stress in Alzheimer's disease.
abstract: Several lines of evidence suggest that the initial events of amyloid-β peptide (Aβ) oligomerization and deposition in Alzheimer's disease (AD) involve the interaction of soluble oligomers with neuronal membranes. In this study, we show that Aβ42 oligomers are recruited to lipid rafts, which are ordered membrane microdomains rich in cholesterol and gangliosides, resulting in lipid peroxidation, Ca(2+) dyshomeostasis and membrane permeabilization in primary fibroblasts from familial AD patients (FAD) bearing APPVal717Ile, PS-1Leu392Val or PS-1Met146Leu gene mutations. Moreover, the presence of significantly higher levels of lipid peroxidation correlated with greater structural modification in detergent resistant domains (DRMs) isolated from APP and PS-1 fibroblasts, compared to WT fibroblasts from healthy subjects. Modulation of raft GM1, including modest depletion of GM1 content and interference with GM1 exposure or negative charge, precluded the interaction of amyloid aggregates with the plasma membrane and the resulting cell damage in FAD fibroblasts and rat brains cortical neurons. These findings suggest a specific role for raft domains as primary mediators of amyloid toxicity in AD neurons.
authors.affiliation: Department of Biochemical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Evangelisti
authors.forename: Daniel
authors.initials: D
authors.lastname: Wright
authors.forename: Mariagioia
authors.initials: M
authors.lastname: Zampagni
authors.forename: Roberta
authors.initials: R
authors.lastname: Cascella
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorillo
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagnoli
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.forename: Daniela
authors.initials: D
authors.lastname: Nichino
authors.forename: Tania
authors.initials: T
authors.lastname: Scartabelli
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: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002772:Cholera Toxin / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016537:Gangliosidosis, GM1 / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D009025:Morpholines; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); C033110:RV 538; D002772:Cholera Toxin; D002118:Calcium