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A clear understanding of the dynamic events of amyloid beta peptide (Abeta) 1-42, such as the folding, self-assembly, and aggregation processes, would be of great significance in Alzheimer's disease (AD) research. However, elucidation of these Abeta1-42 dynamic events is a difficult issue due to uncontrolled polymerization, which also poses a significant obstacle for establishing an experimental system that clarifies the pathological function of Abeta1-42. On the basis of the O-acyl isopeptide method, we herein developed a novel photo-triggered "click peptide" of Abeta1-42, for example, 26-N-Nvoc-26-AIAbeta42, in which the photocleavable 6-nitroveratryloxycarbonyl (Nvoc) group was introduced at the alpha-amino group of Ser26 in 26-O-acyl isoAbeta1-42 (26-AIAbeta42). From the results, (1) the click peptide did not exhibit the self-assembling nature under physiological conditions due to one single modified ester; (2) photoirradiation of the click peptide and subsequent O-N intramolecular acyl migration afforded the intact Abeta1-42 with a quick and one-way conversion reaction (so-called "click"), while the click peptide was stable under nonphotolytic or storage conditions. In addition, it is advantageous that no additional fibril inhibitory auxiliaries were released during conversion to Abeta1-42. This method provides a novel system useful for investigating the dynamic biological functions of Abeta1-42 in AD by inducible activation of Abeta1-42 self-assembly.

The formation of fibrils by amyloid b-protein (Ab) is considered as a key step in the pathology of Alzheimer's disease (AD). Inhibiting the aggregation of Ab 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 Ab-(1-42) fibrils with marked amyloidgenic activity and cytotoxicity. The CHPnanogels incorporated up to 6-8 Ab-(1-42) molecules per particle and induced a change in the conformation of Ab from a random coil to a-helix-or b-sheet-rich structure. This structure was stable even after a 24-h incubation at 37°C and the aggregation of Ab-(1-42) was suppressed. Furthermore, the dissociation of the nanogels caused by the addition of methylb-cyclodextrin released monomeric Ab 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 Ab for inhibiting the formation of fibrils. In addition, CHPNH 2 nanogels protected PC12 cells from Ab toxicity.