Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers

Angelo Demuro, Erene Mina, Rakez Kayed, Saskia C. Milton, Ian Parker, Charles G. Glabe

Research output: Contribution to journalArticle

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Abstract

Increasing evidence suggests that amyloid pepticles 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 μg ml-1) rapidly (∼5s) 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 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 μm). Instead, observations that Aβ42 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.

Original languageEnglish (US)
Pages (from-to)17294-17300
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number17
DOIs
StatePublished - Apr 29 2005
Externally publishedYes

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Oligomers
Amyloid
Calcium
Membranes
Permeability
Monomers
Ions
Islet Amyloid Polypeptide
Prions
Cytotoxicity
Muramidase
Cobalt
Fluorescent Dyes
Toxicity
Cell Death
Agglomeration
Chemical activation
Fluxes
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. / Demuro, Angelo; Mina, Erene; Kayed, Rakez; Milton, Saskia C.; Parker, Ian; Glabe, Charles G.

In: Journal of Biological Chemistry, Vol. 280, No. 17, 29.04.2005, p. 17294-17300.

Research output: Contribution to journalArticle

Demuro, Angelo ; Mina, Erene ; Kayed, Rakez ; Milton, Saskia C. ; Parker, Ian ; Glabe, Charles G. / Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 17. pp. 17294-17300.
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