Ohnishi Takayuki, Yanazawa Masako, Sasahara Tomoya, Kitamura Yasuki, Hiroaki Hidekazu, Fukazawa Yugo, Kii Isao, Nishiyama Takashi, Kakita Akiyoshi, Takeda Hiroyuki, Takeuchi Akihide, Arai Yoshie, Ito Akane, Komura Hitomi, Hirao Hajime, Satomura Kaori, Inoue Masafumi, Muramatsu Shin-ichi, Matsui Ko, Tada Mari, Sato Michio, Saijo Eri, Shigemitsu Yoshiki, Sakai Satoko, Umetsu Yoshitaka, Goda Natsuko, Takino Naomi, Takahashi Hitoshi, Hagiwara Masatoshi, Sawasaki Tatsuya, Iwasaki Genji, Nakamura Yu, Nabeshima Yo-ichi, Teplow David B, Hoshi Minako
Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
Mitsubishi Kagaku Institute of Life Sciences (MITILS; dissolved in March 2010);
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4465-74. doi: 10.1073/pnas.1421182112. Epub 2015 Jul 29.
Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.
神经退行性变与阿尔茨海默病（AD）症状相关，但导致神经退行性变的致病性淀粉样β蛋白（Aβ）寡聚体及其靶点的分子身份仍不清楚。淀粉样球体（ASPD）是源自AD患者的10至15纳米球形Aβ寡聚体，可导致成熟神经元选择性退化。在此，我们表明ASPD的靶点是神经元特异性钠/钾-ATP酶α3亚基（NAKα3）。ASPD与NAKα3的结合损害了NAKα3的特异性活性，激活了N型电压门控钙通道，并导致线粒体钙稳态失调、tau异常和神经退行性变。核磁共振和分子模拟研究表明，球形ASPD包含负责靶点结合的N端Aβ衍生的“刺”，这与低分子量寡聚体和十二聚体不同。NAKα3的第四个细胞外环（Ex4）区域包含天冬酰胺（879）和色氨酸（880），对ASPD-NAKα3相互作用至关重要，因为模拟该Ex4区域的四肽与ASPD表面结合并阻断了ASPD的神经毒性。我们的发现为基于知识设计肽模拟物开辟了新的可能性，这些肽模拟物可通过阻断异常的ASPD-NAKα3相互作用来抑制AD中的神经退行性变。
