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J. Biol. Chem., Vol. 280, Issue 17, 99919, April 29, 2005

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For Amyloid Proteins Longer Isn't Necessarily Better

There are more than 100 human amyloid-related diseases, all caused by normally soluble proteins that have misfolded and aggregated. Originally it was thought that the fibrillar amyloid deposits associated with diseases disrupted intracellular calcium homeostasis and caused neurotoxicity. However, more recent studies have indicated that intermediate soluble oligomers are the culprits. Here, Angelo Demuro and colleagues provide more evidence to implicate these soluble intermediates and to explain just how the oligomers exert their effects on calcium levels.

Amyloid oligomers, but not monomers or fibrils, elevate intracellular free calcium concentration.

The researchers made homogeneous preparations of five disease-related amyloids, including amyloid - and prion peptides, in monomeric, oligomeric, and fibrillar states and examined their effects on cytosolic calcium levels. Isolation of these preparations was done by controlling solvent, handling, and temperature conditions, and aggregation state was verified by physicochemical methods. Demuro et al. found that only the oligomeric forms of the proteins elevated intracellular calcium levels. These oligomers also caused rapid cellular leakage of anionic fluorescent dyes, suggesting a generalized increase in membrane permeability. The authors hypothesize that it is this flux of ions and molecules that leads to the cellular dysfunction and death associated with amyloid-related neurotoxicity.

FOOTNOTES

See referenced article, J. Biol. Chem. 2005, 280, 17294–17300

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This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Papers Of The Week Social Bookmarking                      What's this?