"Click Peptide": pH-Triggered in Situ Production and Aggregation of Monomer Aβ1-42

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