The intense and uncontrollable self-assembling nature of amyloid beta peptide (Abeta) 1-42 is known to cause difficulties in preparing monomeric Abeta1-42; this results in irreproducible or discrepant study outcomes. Herein, we report novel features of a pH click peptide of Abeta1-42 that was designed to overcome these problems. The click peptide is a water-soluble precursor peptide of Abeta1-42 with an O-acyl isopeptide structure between the Gly25-Ser26 sequence. The click peptide adopts and retains a monomeric, random coil state under acidic conditions. Upon change to neutral pH (pH click), the click peptide converts to Abeta1-42 promptly (t(1/2) approximately 10 s) and quantitatively through an O-to-N intramolecular acyl migration. As a result of this quick and irreversible conversion, monomer Abeta1-42 with a random coil structure is produced in situ. Moreover, the oligomerization, amyloid fibril formation and conformational changes of the produced Abeta1-42 can be observed over time. This click peptide strategy should provide a reliable experimental system to investigate the pathological role of Abeta1-42 in Alzheimer's disease.

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