NR ASOU
AU Demuro,A.; Mina,E.; Kayed,R.; Milton,S.C.; Parker,I.; Glabe,C.G.
TI Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers
QU The Journal of Biological Chemistry 2005 Apr 29; 280(17): 17294-300
PT journal article
AB 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.
MH Amyloid/*chemistry; Amyloid beta-Protein/chemistry; Calcium/chemistry/*metabolism; Calcium Channels/metabolism; Carrier Proteins/chemistry; Cell Line, Tumor; Cell Membrane/*metabolism; Cytosol; Dose-Response Relationship, Drug; Fluoresceins/chemistry; Fluorescent Dyes/pharmacology; Humans; Ions; Microscopy, Fluorescence; Neurons/metabolism/*physiology; Peptide Fragments/chemistry; Peptides/chemistry; Permeability; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Time Factors
AD Department of Neurobiology and Behavior and Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA
SP englisch
PO USA