SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function.
SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function.
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DOI：
10.1111/j.1474-9726.2010.00632.x
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发表时间：
2010-12
期刊：
影响因子：
7.8
通讯作者：
Pasinetti GM
中科院分区：
文献类型：
--
作者：
Gong B;Chen F;Pan Y;Arrieta-Cruz I;Yoshida Y;Haroutunian V;Pasinetti GM
BACE 1（β-分泌酶）在阿尔茨海默病（AD）的β-淀粉样蛋白生成中起核心作用。泛素-蛋白酶体系统是一个重要的细胞内蛋白质质量控制系统，最近被认为与BACE 1代谢有关。我们报道了SCFFbx 2-E3连接酶通过F-box相关结构域的Trp 280残基参与BACE 1的结合和泛素化。在生理学上，我们发现Fbx 2在脑神经元的各种细胞内细胞器中表达，并且BACE 1与Fbx 2和淀粉样前体蛋白（APP）共定位，主要在早期的内体和内质网中。前者被认为是APP被BACE 1切割并产生β-淀粉样蛋白的主要细胞内区室。重要的是，我们发现在Tg 2576转基因小鼠的原代皮层和海马神经元中Fbx 2的过表达显著促进BACE 1降解并减少β-淀粉样蛋白的产生。在寻找Fbx 2表达的特异性内源性调节因子的过程中，我们发现，PPARγ共激活因子-1 α（PGC-1α）能够通过涉及Fbx 2基因表达的机制促进BACE 1的降解。有趣的是，我们发现Fbx 2和PGC-1α的表达在衰老的Tg 2576小鼠的大脑中显著降低。我们使用AD小鼠模型的体内研究显示，脑中的外源性腺病毒Fbx 2表达显著降低了BACE 1蛋白水平和活性，同时降低了β-淀粉样蛋白水平并挽救了突触缺陷。我们的研究首次表明，促进大脑中的Fbx 2可能代表了治疗AD的一种新策略。
BACE1 (β-secretase) plays a central role in the β-amyloidogenesis of Alzheimer’s disease (AD). The ubiquitin–proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCFFbx2-E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and β-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARγ coactivator-1α (PGC-1α) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1α was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing β-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD.
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