| First Author | Kaneshiro N | Year | 2022 |
| Journal | iScience | Volume | 25 |
| Issue | 3 | Pages | 103869 |
| PubMed ID | 35243232 | Mgi Jnum | J:324410 |
| Mgi Id | MGI:6887194 | Doi | 10.1016/j.isci.2022.103869 |
| Citation | Kaneshiro N, et al. (2022) Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer's disease. iScience 25(3):103869 |
| abstractText | 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 betaCTF, 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 betaCTF 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 betaCTF 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. |
