화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.438, No.1, 1-5, 2013
Non-toxic conformer of amyloid beta may suppress amyloid beta-induced toxicity in rat primary neurons: Implications for a novel therapeutic strategy for Alzheimer's disease
The 42-mer amyloid beta-protein (A beta 42) oligomers cause neurotoxicity and cognitive impairment in Alzheimer's disease (AD). We previously identified the toxic conformer of A beta 42 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-A beta 42 and E22V-A beta 42 are non-toxic mutants that disfavor the "toxic" turn. Here we hypothesize that these non-toxic mutants of A beta 42 could suppress A beta 42-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-A beta 42 and E22V-A beta 42 suppressed the neurotoxicity and aggregation of A beta 42 as well as the formation of the toxic conformer. The neurotoxicity induced by A beta 42 was also significantly reduced by the treatment of 11A1, but not of A beta-sequence specific antibodies (6E10 and 4G8). Since recent studies indicate that A beta oligomers contain parallel beta-sheet, the present results suggest that the non-toxic mutants of A beta 42 without the "toxic" turn could prevent the propagation process of the toxic conformer of A beta 42 resulting in suppression of the formation of the toxic oligomers. This could be a promising strategy for AD therapeutics. (C) 2013 Elsevier Inc. All rights reserved.