Non-toxic conformer of amyloid beta may suppress amyloid beta-induced toxicity in rat primary neurons: Implications for a novel therapeutic strategy for Alzheimer%26apos;s disease

作者：Izuo Naotaka; Murakami Kazuma; Sato Mizuho; Iwasaki Mami; Izumi Yasuhiko; Shimizu Takahiko; Akaike Akinori; Irie Kazuhiro^*; Kume Toshiaki

来源：Biochemical and Biophysical Research Communications, 2013, 438(1): 1-5.

DOI：10.1016/j.bbrc.2013.05.106

• Alzheimer%26apos
• s disease
• Amyloid beta-protein
• Neurotoxicity
• Oligomer

The 42-mer amyloid beta-protein (A beta 42) oligomers cause neurotoxicity and cognitive impairment in Alzheimer%26apos;s disease (AD). We previously identified the toxic conformer of A beta 42 with a turn at positions 22-23 (%26quot;toxic%26quot; 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 %26quot;toxic%26quot; 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 %26quot;toxic%26quot; 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.

• 出版日期2013-8-16