Formation of “toxic conformer” in amyloid β and its relevance to hereditary mutation at Glu22

Kazuma Murakami¹⁾, Mizuho Sato¹⁾, Takayuki Suzuki¹⁾, Naotaka Izuo²⁾,Toshiaki Kume²⁾, Akinori Akaike²⁾, Tetsu Nagata³⁾, Tomoyuki Nishizaki³⁾,Takami Tomiyama⁴⁾, Hiroshi Mori⁴⁾, Kazuhiro Irie¹⁾

¹⁾Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University
²⁾Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
³⁾Department of Physiology, Hyogo College of Medicine
⁴⁾Department of Neuroscience, Osaka City University Graduate School of Medicine

The 42-mer amyloid β-protein (Aβ42) forms toxic oligomers to cause memory loss in Alzheimer's disease. We previously identified a toxic conformer of Aβ42 with “toxic turn” at Glu22 and Asp23, and demonstrated that monoclonal antibody (11A1) against the toxic turn mainly detected Aβ oligomers in AD brains. The positions of the toxic turn are those at which missense mutations inside the Aβ sequence linked to cerebral amyloid angiopathy are concentrated. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. In this article, we discuss the relevance of these hereditary mutations at Glu22 to formation of the toxic conformer of Aβ42.

Address correspondence to Dr. Kazuhiro Irie, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University (Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan)