Pratim Bose, P., Chatterjee, U., Nerelius, C., Govender, T., Norström, T., Gogoll, A., Sandegren, A., Göthelid, E., Johansson, J., Arvidsson, P.I. (2009). Poly-N-methylated amyloid beta-peptide (Abeta) C-terminal fragments reduce Abeta toxicity in vitro and in Drosophila melanogaster.  J. Med. Chem. 52(24): 8002--8009.

FBrf0209586

Research paper

Alzheimer's disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid beta-peptides (Abeta) into neurotoxic oligo-/polymeric beta-sheet structures is an important pathogenic feature in AD, thus, inhibition of this process has been explored to prevent or treat AD. The C-terminal part plays an important role in Abeta aggregation, but most Abeta aggregation inhibitors have targeted the central region around residues 16-23. Herein, we synthesized hexapeptides with varying extents of N-methylation based on residues 32-37 of Abeta, to target its C-terminal region. We measured the peptides' abilities to retard beta-sheet and fibril formation of Abeta and to reduce Abeta neurotoxicity. A penta-N-methylated peptide was more efficient than peptides with 0, 2, or 3 N-methyl groups. This penta-N-methylated peptide moreover increased life span and locomotor activity in Drosophila melanogaster flies overexpressing human Abeta(1-42).