β-Amyloid (Aβ) peptides play a crucial role in the pathology of the neurodegeneration in Alzheimer's disease (AD). Biological experiments (both in vitro and animal model studies of AD) require synthetic Aβ peptides of standard quality, aggregation grade, neurotoxicity and water solubility. The synthesis of Aβ peptides has been difficult, owing to their hydrophobic character, poor solubility and high tendency for aggregation. Recently an isopeptide precursor (iso-Aβ(1-42)) was synthesized by Fmoc-chemistry and transformed at neutral pH to Aβ(1-42) by O→N acyl migration in a short period of time. We prepared the same precursor peptide using Boc-chemistry and studied the transformation to Aβ(1-42) by acyl migration. The peptide conformation and aggregation processes were studied by several methods (circular dichroism, atomic force and transmission electron microscopy, dynamic light scattering). The biological activity of the synthetic Aβ(1-42) was measured by ex vivo (long-term potentiation studies in rat hippocampal slices) and in vivo experiments (spatial learning of rats). It was proven that O→N acyl migration of the precursor isopeptide results in a water soluble oligomeric mixture of neurotoxic Aβ(1-42). These oligomers are formed in situ just before the biological experiments and their aggregation grade could be standardized.
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience