Poly-N-methylated Amyloid β-Peptide (Aβ) C-Terminal Fragments Reduce Aβ Toxicity in Vitro and in Drosophila melanogaster
2009 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, no 24, 8002-8009 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2009. Vol. 52, no 24, 8002-8009 p.
IdentifiersURN: urn:nbn:se:uu:diva-112210DOI: 10.1021/jm901092hISI: 000272712100016PubMedID: 19908889OAI: oai:DiVA.org:uu-112210DiVA: diva2:285408