APP processing is regulated by cytoplasmic phosphorylation.
APP processing is regulated by cytoplasmic phosphorylation.
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DOI：
10.1083/jcb.200301115
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发表时间：
2003-10-13
期刊：
影响因子：
--
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
作者：
Lee MS;Kao SC;Lemere CA;Xia W;Tseng HC;Zhou Y;Neve R;Ahlijanian MK;Tsai LH
老年斑中淀粉样蛋白-β肽（a β）聚集是阿尔茨海默病（AD）的一个关键特征。在这里，我们发现淀粉样蛋白前体蛋白（APP）对苏氨酸668 （P-APP）的磷酸化可能在APP代谢中发挥作用。在AD大脑中，P-APP在受影响的海马锥体神经元的大泡状结构中积累，这些神经元与抗内核体标记物和β-分泌酶BACE1的抗体结合。Western blot分析显示，在许多AD患者的海马裂解物中，t668磷酸化的APP cooh末端片段水平升高，但对照组没有。重要的是，P-APP在碘二醇梯度下与内核体标记物和BACE1共同作用，并在大鼠初级皮质神经元中与BACE1广泛共定位。此外，与α-分泌酶产生的片段相比，BACE1产生的APP cooh末端片段在T668上优先磷酸化。当T668的磷酸化被突变消除或被T668激酶抑制剂抑制时，Aβ的产生显著减少。综上所述，这些结果表明T668磷酸化可能促进APP的BACE1切割，从而增加Aβ的产生。
Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation.
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