Apolipoprotein receptor 2 and X11 α/β mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production
Apolipoprotein receptor 2 and X11 α/β mediate apolipoprotein E-induced endocytosis of amyloid-β precursor protein and β-secretase, leading to amyloid-β production
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DOI：
10.1523/jneurosci.3993-06.2007
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发表时间：
2007-04-11
影响因子：
5.3
通讯作者：
Tang, Jordan
中科院分区：
文献类型：
--
作者：
He, Xiangyuan;Cooley, Kathleen;Tang, Jordan
β淀粉样蛋白（A β）在脑中的稳态对于阿尔茨海默病（AD）的发病机制至关重要。β是淀粉样β前体蛋白（APP）的一个片段，由两种蛋白酶（β分泌酶和γ分泌酶）在神经元中产生。APP和β-分泌酶都存在于细胞表面，被内吞到内体中以产生A β。神经元触发A β产生的分子机制知之甚少。我们在这里描述的证据表明，载脂蛋白E（ApoE）与受体载脂蛋白E受体2（ApoER 2）的结合触发了APP，β-分泌酶和ApoER 2在神经母细胞瘤细胞中的内吞作用，导致A β的产生。这种机制由衔接蛋白XII α或XII β（X11 α/β）介导，其PTB（磷酸酪氨酸结合）结构域与APP和ApoER 2胞质结构域中新识别的基序结合。同晶型ApoE 4比ApoE 2或ApoE 3触发更多A β的产生;因此，它可能在ApoE 4对散发性AD的遗传风险中发挥作用。该机制独立于Reelin-ApoER 2相互作用发挥作用，也提供了脂质摄取和A β产生之间的联系，这可能对神经元活性的调节很重要。
The homeostasis of amyloid-beta(A beta) in the brain is critical to the pathogenesis of Alzheimer's disease (AD). A beta is a fragment of amyloid-beta precursor protein (APP) generated in neurons by two proteases, beta- and gamma-secretases. APP and beta-secretase, both present on cell surface, are endocytosed into endosomes to produce A beta. The molecular mechanism by which neurons trigger the production of A beta is poorly understood. We describe here evidence that the binding of lipid-carrying apolipoprotein E (ApoE) to receptor apolipoprotein E receptor 2 (ApoER2) triggers the endocytosis of APP, beta-secretase, and ApoER2 in neuroblastoma cells, leading to the production of A beta. This mechanism, mediated by adaptor protein XII alpha or XII beta (X11 alpha/beta), whose PTB (phosphotyrosine-binding) domain binds to APP and a newly recognized motif in the cytosolic domain of ApoER2. Isomorphic form ApoE4 triggers the production of more A beta than by ApoE2 or ApoE3; thus, it may play a role in the genetic risk of ApoE4 for the sporadic AD. The mechanism, which functions independently from Reelin-ApoER2 interaction, also provides a link between lipid uptake and A beta production, which may be important for the regulation of neuronal activity.