@article{8a051356b54d4bb593f050fc6cb2f9e9,
title = "Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer's disease",
abstract = "Endosomal anomalies because of vesicular traffic impairment have been indicated as an early pathology of Alzheimer{\textquoteright}| 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.",
keywords = "Biochemistry, Biological sciences, Neuroscience",
author = "Nanaka Kaneshiro and Masato Komai and Ryosuke Imaoka and Atsuya Ikeda and Yuji Kamikubo and Takashi Saito and Saido, {Takaomi C.} and Taisuke Tomita and Tadafumi Hashimoto and Takeshi Iwatsubo and Takashi Sakurai and Takashi Uehara and Nobumasa Takasugi",
note = "Funding Information: We are grateful to Dr. N. Nukina (Doshisha University) and the Legend research grant in 2019 for providing research materials. This work was supported by the Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science ( 17K08272 and 20K07014 ), Research Grant from the Ryobi Teien Memorial Foundation , Life Science Foundation of Japan (N. T), Grant-in-Aid for Scientific Research (C) ( 20K07765 to Y. K), Grant-in-Aid for Scientific Research (B) ( 21H02815 to T. S), Grants-in-aid for Scientific Research (A) ( 119H01015 to T. T), Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development ( JP21dm0207073 to T. T), and Grant-in-Aid for JSPS Fellows (N.K). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "18",
doi = "10.1016/j.isci.2022.103869",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "3",
}