Biophysical Characterization of Aβ42 C-Terminal Fragments: Inhibitors of Aβ42 Neurotoxicity

A key event in Alzheimer's disease (AD) is age-dependent, brain accumulation of amyloid beta-protein (A beta) leading to A beta self-association into neurotoxic oligomers. Previously, we showed that A beta oligomerization and neurotoxicity could be inhibited by C-terminal fragments (CTFs) of A beta 42. 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 or CTF aqueous solubility, aggregation kinetics, and morphology oil peptide length and sequence and the correlation between these characteristics and inhibition of A beta 42-induced toxicity. We found that CTFs up to 8 residues long were soluble at concentrations > 100 mu M and had a low propensity to aggregate. Longer CTFs were soluble at similar to 1-80 mu M, and most, but not all, readily formed beta-sheet-rich fibrils. Comparison to A beta 40-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 A beta 42-induced neurotoxicity. The data enhance our understanding of the physical charactertistics that affect CTF activity and advance our ability to design, synthesize, and test future generations of inhibitors.