Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer’s disease
Nanaka Kaneshiro,
Masato Komai,
Ryosuke Imaoka,
Atsuya Ikeda,
Yuji Kamikubo,
Takashi Saito,
Takaomi C. Saido,
Taisuke Tomita,
Tadafumi Hashimoto,
Takeshi Iwatsubo,
Takashi Sakurai,
Takashi Uehara,
Nobumasa Takasugi
Affiliations
Nanaka Kaneshiro
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan; Research Fellow of Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan
Masato Komai
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Ryosuke Imaoka
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Atsuya Ikeda
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Yuji Kamikubo
Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan
Takashi Saito
Department of Neurocognitive Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan
Takaomi C. Saido
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan
Taisuke Tomita
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
Tadafumi Hashimoto
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-0033, Japan
Takeshi Iwatsubo
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-0033, Japan
Takashi Sakurai
Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan
Takashi Uehara
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Nobumasa Takasugi
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan; Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan; Corresponding author
Summary: Endosomal anomalies because of vesicular traffic impairment have been indicated as an early pathology of Alzheimer’| disease (AD). However, the mechanisms and therapeutic targets remain unclear. We previously reported that βCTF, one of the pathogenic metabolites of APP, interacts with TMEM30A. TMEM30A constitutes a lipid flippase with P4-ATPase and regulates vesicular trafficking through the asymmetric distribution of phospholipids. Therefore, the alteration of lipid flippase activity in AD pathology has got attention. Herein, we showed that the interaction between βCTF and TMEM30A suppresses the physiological formation and activity of lipid flippase in AD model cells, A7, and AppNL−G-F/NL−G-F model mice. Furthermore, the T-RAP peptide derived from the βCTF binding site of TMEM30A improved endosomal anomalies, which could be a result of the restored lipid flippase activity. Our results provide insights into the mechanisms of vesicular traffic impairment and suggest a therapeutic target for AD.
