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

• Published in: Journal of medicinal chemistry Vol. 52; no. 24; pp. 8002 - 8009
• Main Authors: Pratim Bose, Partha, Chatterjee, Urmimala, Nerelius, Charlotte, Govender, Thavendran, Norström, Thomas, Gogoll, Adolf, Sandegren, Anna, Göthelid, Emmanuelle, Johansson, Jan, Arvidsson, Per I
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2009; Amer Chemical Soc
• Subjects: Biological and medical sciences; Chemistry; Chemistry, Medicinal; Kemi; Life Sciences & Biomedicine; Läkemedelskemi; Medical sciences; Medicinal Chemistry; NATURAL SCIENCES; NATURVETENSKAP; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Science & Technology; OXIDATIVE STRESS; MECHANISM; PROTEIN SECONDARY STRUCTURE; AMINO; INHIBITORS; MODEL; FIBRILLOGENESIS; ALZHEIMERS; OLIGOMERS; AGGREGATION; Peptides; Rat; Adrenal glands; Toxicity; Insecta; Nervous system; Neurotoxicity; Structure activity relation; Molecular aggregation; Inhibition; Chemical synthesis; Rodentia; Antialzheimer agent; In vitro; Hexapeptide; Drosophilidae; Vertebrata; Mammalia; Cell line; Neuron; β Amyloid protein; Arthropoda; Peptide synthesis; Invertebrata; Methylation; Drosophila melanogaster; Diptera
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm901092h

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.