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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 (Aβ, 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 μgml^–1) rapidly (∼5 s) elevated intracellular Ca²⁺, whereas equivalent amounts of monomers and fibrils did not. Ca²⁺ signals evoked by Aβ42 oligomers persisted after depletion of intracellular Ca²⁺ stores, and small signals remained in Ca²⁺-free medium, indicating contributions from both extracellular and …