[Development of click peptide: stimuli-responsive precursor producing Alzheimer's disease-related amyloid beta peptide].
In a pathological mechanism of Alzheimer's disease (AD), amyloid beta peptide (Abeta) 1-42 plays a crucial role. However, the detailed pathological mechanism remains unclear. This elucidation is hampered by handling difficulties of Abeta1-42 due to its poor water-solubility and uncontrollable aggregation. These properties prevent reproducing neurotoxicity-related assembly events of Abeta1-42 in the experiments, leading to discrepant study outcomes. Namely, such properties of Abeta1-42 are serious obstacles to establish an experiment system that clarifies the pathological mechanism of Abeta1-42 in AD. To solve these problems, we developed "click peptide" of Abeta1-42 based on the "Omicron-acyl isopeptide method". The click peptide, which contains an Omicron-acyl instead of N-acyl residue at Gly(25)-Ser(26) of Abeta1-42, is converted to Abeta1-42 via an Omicron-to-N intramolecular acyl migration upon being triggered by pH-change (pH-click) or photo-irradiation (photo-click). The click peptide was 100-fold more water-soluble than Abeta1-42 and clearly adopted a monomeric random coil structure due to the Omicron-acyl moiety in the peptide backbone. The click peptide was quickly converted to monomer Abeta1-42 with a random coil structure under physiological conditions upon an action (click). The obtained Abeta1-42 underwent both self-assembly and conformational changes with time. Because the in situ production of intact Abeta1-42 from the water-soluble and non-aggregative precursor could overcome the handling problems of Abeta1-42, this click peptide strategy would provide a reliable experiment system to investigate the pathological functions of Abeta1-42 in AD.
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan. ky01220@poppy.kyoto-phu.ac.jp
Atsuhiko
A
Taniguchi
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D012995:Solubility; D014867:Water
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); D014867:Water