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

被引：8

作者：

Kaneshiro, Nanaka ^{[1
,2
]}

Komai, Masato ^{[1
]}

Imaoka, Ryosuke ^{[1
]}

Ikeda, Atsuya ^{[1
]}

Kamikubo, Yuji ^{[3
]}

Saito, Takashi ^{[4
,5
]}

Saido, Takaomi C. ^{[5
]}

Tomita, Taisuke ^{[6
]}

Hashimoto, Tadafumi ^{[7
]}

Iwatsubo, Takeshi ^{[7
]}

Sakurai, Takashi ^{[3
]}

Uehara, Takashi ^{[1
]}

Takasugi, Nobumasa ^{[1
,3
]}

机构：

[1] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med Pharmacol, Kita Ku, 1-1-1 Tsushima Naka, Okayama 7008530, Japan

[2] Japan Soc Promot Sci, Chiyoda Ku, Tokyo 1020083, Japan

[3] Juntendo Univ, Dept Cellular & Mol Pharmacol, Grad Sch Med, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan

[4] Nagoya City Univ, Dept Neurocognit Sci, Grad Sch Med Sci, Nagoya, Aichi, Japan

[5] RIKEN Ctr Brain Sci, Lab Proteolyt Neurosci, Wako, Saitama, Japan

[6] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Neuropathol & Neurosci, Tokyo 1130033, Japan

[7] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan

来源：

ISCIENCE | 2022年 / 25卷 / 03期

基金：

日本学术振兴会;

关键词：

AMYLOID-PRECURSOR PROTEIN; BETA-SECRETASE; A-BETA; SUBCELLULAR-LOCALIZATION; CDC50; PROTEINS; DOWN-SYNDROME; APP; PHOSPHATIDYLSERINE; TRANSPORT; CLEAVAGE;

D O I：

10.1016/j.isci.2022.103869

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Endosomal anomalies because of vesicular traffic impairment have been indicated as an early pathology of Alzheimer'vertical bar disease (AD). However, the mechanisms and therapeutic targets remain unclear. We previously reported thatbCTF, 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 beta CTF and TMEM30A suppresses the physiological formation and activity of lipid flippase in AD model cells, A7, and App(NLG-F/NLG-F) model mice. Furthermore, the T-RAP peptide derived from the beta CTF 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.

引用

页数：21

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