title: Inhibition of the formation of amyloid beta-protein fibrils using biocompatible nanogels as artificial chaperones.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ikeda
authors.forename: Takuma
authors.initials: T
authors.lastname: Okada
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Sawada
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Matsuzaki
mesh_terms: D016229:Amyloid beta-Peptides / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000648:ultrastructure; D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D016923:Cell Death; D002784:Cholesterol / Q000737:chemistry; D002850:Chromatography, Gel; D002942:Circular Dichroism; D003374:Coumarins / Q000378:metabolism; D005936:Glucans / Q000737:chemistry; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D018832:Molecular Chaperones / Q000494:pharmacology*; D000080385:Nanogels; D009454:Neurofibrils / Q000187:drug effects*; D016716:PC12 Cells; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011094:Polyethyleneimine / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051381:Rats; D013050:Spectrometry, Fluorescence; D013696:Temperature
chemical_list: D016229:Amyloid beta-Peptides; D001672:Biocompatible Materials; D003374:Coumarins; D005936:Glucans; D018832:Molecular Chaperones; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; C088959:7-diethylaminocoumarin-3-carboxylic acid; C009109:pullulan; D011094:Polyethyleneimine; D002784:Cholesterol