The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

Aggregated beta-amyloid (A beta) peptides are neurotoxic and cause neuronal death both in vitro and in vivo. Although the formation of a beta-sheet structure is usual required to form aggregates, the relationship between neurotoxicity and the AD sequence remains unclear. To explore the correlation between A beta sequence, secondary structure, aggregative ability, and neurotoxicity, we utilized both full-length and fragment-truncated A beta peptides. Using a combination of spectroscopic and cellular techniques, we demonstrated that neurotoxicity and aggregative ability are correlated while the relationship between these characteristics and secondary structure is not significant. The hydrophobic C-terminus, particularly the amino acids of 17-21, 25-35, and 41-42, is the main region responsible for neurotoxicity and aggregation. Deleting residues 17-21, 25-35 or 41-42 significantly reduced the toxicity. On the other hand, truncation of the peptides at either residues 22-24 or residues 36-40 had little effect on toxicity and aggregative ability. While the N-terminal residues 1-16 may not play a major role in neurotoxicity and aggregation, a lack of N-terminal fragment A beta peptide, (e.g. A beta 17-35), does not display the neurotoxicity of either full-length or 17-21, 25-35 truncated A beta peptides. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.