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

doi:10.1016/j.isci.2022.103869

Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer's disease

iScience. 2022 Feb 4;25(3):103869. doi: 10.1016/j.isci.2022.103869. eCollection 2022 Mar 18.

Authors

Nanaka Kaneshiro^{1

2}, Masato Komai¹, Ryosuke Imaoka¹, Atsuya Ikeda¹, Yuji Kamikubo³, Takashi Saito^{4

5}, Takaomi C Saido⁵, Taisuke Tomita⁶, Tadafumi Hashimoto⁷, Takeshi Iwatsubo⁷, Takashi Sakurai³, Takashi Uehara¹, Nobumasa Takasugi^{1

3}

Affiliations

¹ 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.
² Research Fellow of Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan.
³ Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan.
⁴ Department of Neurocognitive Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
⁵ Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan.
⁶ Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
⁷ Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-0033, Japan.

Abstract

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 App^{NL-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.

Keywords: Biochemistry; Biological sciences; Neuroscience.