title: Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers.
abstract: Increasing evidence suggests that amyloid peptides associated with a variety of degenerative diseases induce neurotoxicity in their intermediate oligomeric state, rather than as monomers or fibrils. To test this hypothesis and investigate the possible involvement of Ca2+ signaling disruptions in amyloid-induced cytotoxicity, we made homogeneous preparations of disease-related amyloids (Abeta, prion, islet amyloid polypeptide, polyglutamine, and lysozyme) in various aggregation states and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.6-6 microg ml-1) rapidly (approximately 5 s) elevated intracellular Ca2+, whereas equivalent amounts of monomers and fibrils did not. Ca2+ signals evoked by Abeta42 oligomers persisted after depletion of intracellular Ca2+ stores, and small signals remained in Ca2+-free medium, indicating contributions from both extracellular and intracellular Ca2+ sources. The increased membrane permeability to Ca2+ cannot be attributed to activation of endogenous Ca2+ channels, because responses were unaffected by the potent Ca2+-channel blocker cobalt (20 microm). Instead, observations that Abeta42 and other oligomers caused rapid cellular leakage of anionic fluorescent dyes point to a generalized increase in membrane permeability. The resulting unregulated flux of ions and molecules may provide a common mechanism for oligomer-mediated toxicity in many amyloidogenic diseases, with dysregulation of Ca2+ ions playing a crucial role because of their strong trans-membrane concentration gradient and involvement in cell dysfunction and death.
authors.affiliation: Department of Neurobiology and Behavior and Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Demuro
authors.forename: Erene
authors.initials: E
authors.lastname: Mina
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Saskia C
authors.initials: SC
authors.lastname: Milton
authors.forename: Ian
authors.initials: I
authors.lastname: Parker
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D003600:Cytosol; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D007477:Ions; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010539:Permeability; D013997:Time Factors
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D002352:Carrier Proteins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007477:Ions; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); D002118:Calcium; C007740:fluorexon