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  • Inhibition of the formation of amyloid beta-protein fibrils using biocompatible nanogels as artificial chaperones.

Inhibition of the formation of amyloid beta-protein fibrils using biocompatible nanogels as artificial chaperones.

FEBS letters (2006-11-28)
Keisuke Ikeda, Takuma Okada, Shin-Ichi Sawada, Kazunari Akiyoshi, Katsumi Matsuzaki
ABSTRACT

The formation of fibrils by amyloid beta-protein (Abeta) is considered as a key step in the pathology of Alzheimer's disease (AD). Inhibiting the aggregation of Abeta 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 Abeta-(1-42) fibrils with marked amyloidgenic activity and cytotoxicity. The CHP-nanogels incorporated up to 6-8 Abeta-(1-42) molecules per particle and induced a change in the conformation of Abeta 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 Abeta-(1-42) was suppressed. Furthermore, the dissociation of the nanogels caused by the addition of methyl-beta-cyclodextrin released monomeric Abeta molecules. Nanogels composed of amino-group-modified CHP (CHPNH(2)) with positive charges under physiological conditions had a greater inhibitory effect than CHP-nanogels, suggesting the importance of electrostatic interactions between CHPNH(2) and Abeta for inhibiting the formation of fibrils. In addition, CHPNH(2) nanogels protected PC12 cells from Abeta toxicity.

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7-(Diethylamino)coumarin-3-carboxylic acid, BioReagent, suitable for fluorescence, ≥98.0% (HPCE)
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