Biophysical characterization of Abeta42 C-terminal fragments: inhibitors of Abeta42 neurotoxicity.
A key event in Alzheimer's disease (AD) is age-dependent, brain accumulation of amyloid beta-protein (Abeta) leading to Abeta self-association into neurotoxic oligomers. Previously, we showed that Abeta oligomerization and neurotoxicity could be inhibited by C-terminal fragments (CTFs) of Abeta42. Because these CTFs are highly hydrophobic, we asked if they themselves aggregated and, if so, what parameters regulated their aggregation. To answer these questions, we investigated the dependence of CTF aqueous solubility, aggregation kinetics, and morphology on peptide length and sequence and the correlation between these characteristics and inhibition of Abeta42-induced toxicity. We found that CTFs up to 8 residues long were soluble at concentrations >100 microM and had a low propensity to aggregate. Longer CTFs were soluble at approximately 1-80 microM, and most, but not all, readily formed beta-sheet-rich fibrils. Comparison to Abeta40-derived CTFs showed that the C-terminal dipeptide I41-A42 strongly promoted aggregation. Aggregation propensity correlated with the previously reported tendency to form beta-hairpin conformation but not with inhibition of Abeta42-induced neurotoxicity. The data enhance our understanding of the physical characteristics that affect CTF activity and advance our ability to design, synthesize, and test future generations of inhibitors.
Li
Huiyuan
H
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive, Los Angeles, California 90095, USA.
Monien
Bernhard H
BH
Fradinger
Erica A
EA
Urbanc
Brigita
B
Bitan
Gal
G
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006131:Growth Inhibitors / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology* / Q000633:toxicity / Q000648:ultrastructure; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability; D017433:Protein Structure, Secondary / Q000187:drug effects; D051381:Rats; D012995:Solubility
D016229:Amyloid beta-Peptides; D006131:Growth Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)