title: Plasma membrane injury depends on bilayer lipid composition in Alzheimer's disease.
abstract: Increasing evidence indicates that interaction of amyloid-β peptide (Aβ) with the cell membrane is a primary step in Alzheimer's disease (AD) neurotoxicity. In particular, it has been demonstrated that lipid rafts are key sites of Aβ production, aggregation, and interaction with the cell membrane. In this study we show that Aβ42 oligomers are recruited to lipid rafts, leading to plasma membrane perturbation and Ca2+ dyshomeostasis in primary fibroblasts from familial AD patients bearing APPVal717Ile, PS-1Leu392Val, or PS-1Met146Leu gene mutations. In contrast, a moderate increase in membrane cholesterol content precluded the interaction of Aβ42 oligomers with the plasma membrane and resulting cell damage. Moreover, the recruitment of amyloid assemblies to lipid raft domains of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper increase in intracellular Ca2+ levels and plasma membrane permeabilization. Our findings suggest a protective role for raft cholesterol against amyloid toxicity in AD.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Evangelisti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Mariagioia
authors.initials: M
authors.lastname: Zampagni
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cascella
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Becatti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorillo
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caselli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagnoli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cecchi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D021962:Membrane Microdomains / Q000502:physiology; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: C450760:APP protein, Neisseria meningitidis; D016229:Amyloid beta-Peptides; D001425:Bacterial Outer Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D018621:PrPC Proteins; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D002784:Cholesterol; D002118:Calcium
keywords: Alzheimer's disease fibroblasts; Aβ$_{42}$-GM1 colocalization; calcium dysregulation; lipid rafts; membrane cholesterol; membrane permeabilization; prion