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Poly-N-methylated Amyloid β-Peptide (Aβ) C-Terminal Fragments Reduce Aβ Toxicity in Vitro and in Drosophila melanogaster

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posted on 2009-12-24, 00:00 authored by Partha Pratim Bose, Urmimala Chatterjee, Charlotte Nerelius, Thavendran Govender, Thomas Norström, Adolf Gogoll, Anna Sandegren, Emmanuelle Göthelid, Jan Johansson, Per I. Arvidsson
Alzheimer’s disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid β-peptides (Aβ) into neurotoxic oligo-/polymeric β-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 Aβ aggregation, but most Aβ 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 Aβ, to target its C-terminal region. We measured the peptides' abilities to retard β-sheet and fibril formation of Aβ and to reduce Aβ 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 Aβ1−42.

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