Synthesis, aggregation, and neurotoxicity of the Alzheimer's Aβ1-42 amyloid peptide and its isoaspartyl isomers

Amyloid A beta 1-42 peptide (A beta 1-42) and its isomers with an isoaspartyl residue at position 7 or 23 [A beta 1-42(isoAsp7) and A beta 1-42(isoAsp23)] were synthesized in high purity by the Fmoc-solid phase technique, followed by HPLC on a silica-based reversed-phase column under the basic conditions. Importantly, A beta 1-42(isoAsp23) aggregated more strongly than native A beta 1-42 and showed significant neurotoxicity, while the aggregation ability and neurotoxicity of A beta 1-42(isoAsp7) was weak. This suggests that the isomerization of the aspartyl residues plays an important role in fibril formation in Alzheimer's disease. (C) 1999 Elsevier Science Ltd. All rights reserved.