Study on cholesterol-dependent regulatory mechanisms of amyloid precursor protein processing in membrane microdomains

膜微区淀粉样前体蛋白加工的胆固醇依赖性调节机制研究

• 批准号: 18500283
• 负责人: SAKURAI Takashi
• 金额: $ 2.63万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18500283/
• 关键词: amvloid; Alzheimer's disease; microdomains; 膜ラフト

Cholesterol-dependent cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1) in lipid rafts is thought to be a critical regulatory event in generating amyloid-beta peptide, which plays a key role in the pathogenesis of Alzheimer's disease. To investigate the underlying molecular mechanisms of this process in neurons, we analyzed immunoisolated, APP-containing, detergent-resistant membranes from mouse and rat brains. APP was incorporated into cholesterol-dependent lipid-protein complexes linked through a network of protein interactions, which largely excluded BACE1. In copatching experiments, APP was preferentially associated with microdomains marked by GPI-anchored prion protein and not BACE 1-containing microdomains. Protein interactions were necessary for association with the prion-containing microdomains and mediated inhibitory effects on APP-BACE1 interaction and beta-cleavage. Thus we propose a novel regulatory mechanism of APP processing through differential association with distinct microdomains controlled by protein interactions.

胆固醇依赖的淀粉样前体蛋白(APP)在脂筏中被β-分泌酶(BACE1)切割，被认为是产生淀粉样β多肽的关键调节事件，而淀粉样β多肽在阿尔茨海默病的发病机制中起着关键作用。为了研究这一过程在神经元中的潜在分子机制，我们分析了免疫隔离的、含有APP的、耐洗涤剂的小鼠和大鼠大脑的膜。APP被结合到通过蛋白质相互作用网络连接的胆固醇依赖的脂-蛋白质复合体中，这在很大程度上排除了BACE1。在配对实验中，APP优先与GPI锚定的普恩蛋白标记的微域相关，而不是含有BACE 1的微域。蛋白质之间的相互作用是与含有Prion的微区结合所必需的，并介导了对APP-BACE1相互作用和β-切割的抑制作用。因此，我们提出了一种新的APP加工调控机制，通过与蛋白质相互作用控制的不同微域的不同关联来实现。

项目成果

Sodium channel β4 subunit : downregulation and possible involvement of neuritic degeneration in Huntington disease transgenic mice

钠通道β4亚基：亨廷顿病转基因小鼠的下调和可能涉及神经变性

• 发表时间: 2006
• 期刊: J Neurochem 98
• 作者: Oyama;F;et. al.
• 通讯作者: et. al.

Beta cleavage by BACE1:New processing mechanism and BACE1 structure

BACE1 的 Beta 裂解：新的加工机制和 BACE1 结构

• 发表时间: 2007
• 作者: Sakurai;T;et. al.;貫名 信行
• 通讯作者: 貫名 信行

β切断の機能と調節機構

β-裂解的功能及调控机制

• 发表时间: 2007
• 期刊: 実験医学増刊脳神経疾患の分子病態と治療への展開 25
• 作者: Shimizu;H;et. al.;櫻井 隆;Morishima-Kawashima M;Miyazaki H;櫻井 隆
• 通讯作者: 櫻井 隆

膜ミクロドメイン依存性の新規アミロイド前駆体蛋白質代謝制御機構

膜微区依赖的新型淀粉样前体蛋白代谢控制机制

• 发表时间: 2007
• 作者: Sakurai;T;et. al.;櫻井 隆
• 通讯作者: 櫻井 隆

Sodium channel β4 subunit : downregulation and possible involvement of neuritic degeneration in Huntington disease transgenic mice.

钠通道 β4 亚基：亨廷顿病转基因小鼠中的下调并可能涉及神经炎变性。

• 发表时间: 2006
• 期刊: J Neurochem 98
• 作者: Oyama;F;et. al.;Oyama F
• 通讯作者: Oyama F