摘要：SummaryEndosomal 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-Fmodel 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.Graphical abstractDisplay OmittedHighlights•Interaction between βCTF and TMEM30A mediates endosomal anomalies•Accumulated βCTF impairs lipid flippase function, a regulator of vesicle transport•Age-dependent lipid flippase disorder can precede Aβ deposition in AD model mice•βCTF interacting peptide, 'T-RAP′ can improve βCTF mediated endosomal anomaliesBiological sciencesBiochemistryNeuroscience
