Non-toxic conformer of amyloid β may suppress amyloid β-induced toxicity in rat primary neurons: implications for a novel therapeutic strategy for Alzheimer's disease

Abstract

The 42-mer amyloid β-protein (Aβ42) oligomers cause neurotoxicity and cognitive impairment in Alzheimer's disease (AD). We previously identified the toxic conformer of Aβ42 with a turn at positions 22-23 ("toxic" turn) to form oligomers and to induce toxicity in rat primary neurons, along with the non-toxic conformer with a turn at positions 25-26. G25P-Aβ42 and E22V-Aβ42 are non-toxic mutants that disfavor the "toxic" turn. Here we hypothesize that these non-toxic mutants of Aβ42 could suppress Aβ42-induced neurotoxicity, and examined their effects on the neurotoxicity, aggregation, and levels of the toxic conformer, which was evaluated by dot blotting using a monoclonal antibody (11A1) against the toxic conformer. G25P-Aβ42 and E22V-Aβ42 suppressed the neurotoxicity and aggregation of Aβ42 as well as the formation of the toxic conformer. The neurotoxicity induced by Aβ42 was also significantly reduced by the treatment of 11A1, but not of Aβ-sequence specific antibodies (6E10 and 4G8). Since recent studies indicate that Aβ oligomers contain parallel β-sheet, the present results suggest that the non-toxic mutants of Aβ42 without the "toxic" turn could prevent the propagation process of the toxic conformer of Aβ42 resulting in suppression of the formation of the toxic oligomers. This could be a promising strategy for AD therapeutics.

Keywords: 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 40-mer amyloid β-protein; 42-mer amyloid β-protein; AD; Alzheimer’s disease; Amyloid β-protein; Aβ40; Aβ42; DIV; IgG; MTT; NMR; Neurotoxicity; Oligomer; PBS; Th-T; Veh; Wt; days in vitro; iPSCs; immunoglobulin G; induced pluripotent stem cells; nuclear magnetic resonance; phosphate-buffered saline; thioflavin T; vehicle; wild-type.