Poly-N-methylated amyloid beta-peptide (Abeta) C-terminal fragments reduce Abeta toxicity in vitro and in Drosophila melanogaster.
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).
Pratim Bose
Partha
P
Department of Biochemistry and Organic Chemistry, Uppsala University, Uppsala, Sweden.
Chatterjee
Urmimala
U
Nerelius
Charlotte
C
Govender
Thavendran
T
Norström
Thomas
T
Gogoll
Adolf
A
Sandegren
Anna
A
Göthelid
Emmanuelle
E
Johansson
Jan
J
Arvidsson
Per I
PI
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002942:Circular Dichroism; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D008745:Methylation; D018625:Microscopy, Atomic Force; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)