'Click Peptide' Based on 'O-Acyl Isopeptide Method': In Situ Production of Monomer Amyloid β Peptide from Water-Soluble Precursor Analogues

摘要

Amyloid β peptides (Aβs) are the main proteinaceous components of amyloid plaques found in the brains of Alzheimer's disease (AD) patients. Although many studies support the notion that Aβs are crucial in the pathogenesis of AD [1], the details remain in controversies. To investigate its pathology, Aβs samples should be used in their monomelic random coil states, because the neurotoxicity of Aβs is directly related to their assembly states (monomer, oligomer and aggregate). However, it is difficult to prepare monomelic Aβs with random coil structures due to their low water-solubility and uncontrollable aggregation. These handling problems result in discrepant outcomes in Aβ studies. Hence, we conceived the idea that an "in situ" production system that affords only monomelic Aβs from water-soluble and non-aggregative precursors would be a superb tool in understanding the pathological role of Aβs. To achieve this system, we developed a water-soluble "click peptide" [2-6] of Aβ 1-42 on the basis of an "O-acyl isopeptide method" [7] (Figure 1). The peptide has an O-acyl isopeptide structure at Gly~(25) -Ser ~(26), and converts to intact Aβ 1-42 via an O-to-N intramolecular acyl migration upon a stimulus ("click"; e.g. pH-change or photo-irradiation). Here, we verified the useful features of pH-click peptide (1) for Aβ studies.