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

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Article number103869
JournaliScience
Volume25
Issue number3
DOIs
Publication statusPublished - Mar 18 2022

Keywords

  • Biochemistry
  • Biological sciences
  • Neuroscience

ASJC Scopus subject areas

  • General

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