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Inhibition of the formation of amyloid beta-protein fibrils using biocompatible nanogels as artificial chaperones
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The formation of fibrils by amyloid P-protein (A beta) is considered as a key step in the pathology of Alzheimer's disease (AD). Inhibiting the aggregation of A beta is a promising approach for AD therapy. In this study, we used biocompatible nanogels composed of a polysaccharide pullulan backbone with hydrophobic cholesterol moieties (cholesterol-bearing pullulan, CHP) as artificial chaperones to inhibit the formation of A beta-(1-42) fibrils with marked amyloidgenic activity and cytotoxicity. The CHP-nanogels incorporated up to 6-8 A beta-(1-42) molecules per particle and induced a change in the conformation of A beta from a random coil to alpha-helix- or beta-sheet-rich structure. This structure was stable even after a 24-h incubation at 37 degrees C and the aggregation of A beta-(1-42) was suppressed. Furthermore, the dissociation of the nanogels caused by the addition of methyl-beta-cyclodextrin released monomeric A beta molecules. Nanogels composed of amino-group-modified CHP (CHPNH2) with positive charges under physiological conditions had a greater inhibitory effect than CHP-nanogels, suggesting the importance of electrostatic interactions between CHPNH2 and A beta for inhibiting the formation of fibrils. In addition, CHPNH2 nanogels protected PC12 cells from A beta toxicity.
This ex vivo study showed that biocompatible nanogels 20-30 nm in diameter can prevent aggregation of proteins associated with Alzheimer's disease and inhibit amyloid fibers from formimg. Chaperones are proteins that help other proteins properly fold.
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FEBS LETTERS 580 (28-29): 6587-6595 DEC 11 2006
Ikeda K, Okada T, Sawada S, Akiyoshi K, Matsuzaki K
Last updated on September 25, 2007
This work is supported in part by the Nanoscale Science and Engineering Initiative of the National Science Foundation
under NSF Award Number EEC-0118007.
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