Regulation of intracellular APP metabolism by phosphorylation

β-淀粉样前体蛋白(APP)在其胞浆区域含有三个已知的磷酸化位点。我们在这里报道，APP的三个位点之一Thr668的磷酸化是神经元特有的现象。在成年大鼠神经组织和原代培养的大鼠海马神经元中，APP的磷酸化形式(PiAPP)定位于体细胞质膜和突起，而APP分布于胞体和突起。抑制轴突转运导致原代培养的大鼠海马神经元中PiAPP完全消失，灯盏花素A阻断跨细胞作用改变了PiAPP在神经元中的分布。我们的发现表明，APP在快速轴突运输后在神经末梢被磷酸化，PiAPP通过跨细胞作用重新分布到质膜和树突中。由于β-淀粉样蛋白(Abeta)的产生在生理上仅限于神经细胞，而且APP的磷酸化也是神经元特有的事件，因此分析APP的磷酸化机制可能有助于理解阿尔茨海默病(AD)抗体产生的分子机制。

beta-amyloid precursor protein (APP) containes three known phosphorylation sites in its cytoplasmic domain. We report here that phosphorylation of APP at Thr668, one of the three sites, is a neuron-specific phenomenon. In adult rat neuronal tissues and in primary cultures of rat hippocampal neuron, the phosphorylated form of APP (PiAPP) is localized in somatic plasma membrane and on neurites although APP distributes in somata and on neurites. Inhibition of axonal tranport results in complete disaappearance of PiAPP in primary cultures of rat hippocampal neuron, and disruption of transcytosis with brefeldin A altered the distribution of PiAPP in the neuron. Our findings indicate that APP is phosphorylated at the nerve terminal after fast axonal transport, and PiAPP is redistributed into plasma membrane and dendrites by transcytosis. Because the production of beta-amyloid (Abeta) is physiologically restricted to neuronal cells and because the phosphorylation of APP also is a neuronally specific event, analysis of the mechanism of APP phosphorylation may contribute to understanding the molecular mechanism of Ab production in Alzheimer's disease (AD).