Muresan Zoia, Muresan Virgil
Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
Mol Biol Cell. 2007 Oct;18(10):3835-44. doi: 10.1091/mbc.e06-07-0625. Epub 2007 Jul 18.
Phosphorylation of amyloid-beta precursor protein (APP) at Thr(668) is a normal process linked to neurite extension and anterograde transport of vesicular cargo. By contrast, increased phosphorylation of APP is a pathological trait of Alzheimer's disease. APP is overexpressed in Down's syndrome, a condition that occasionally leads to increased APP phosphorylation, in cultured cells. Whether phosphorylation of APP in normal versus high APP conditions occurs by similar or distinct signaling pathways is not known. Here, we addressed this problem using brainstem-derived neurons (CAD cells). CAD cells that ectopically overexpress APP frequently show features of degenerating neurons. We found that, in degenerating cells, APP is hyperphosphorylated and colocalizes with early endosomes. By contrast, in normal CAD cells, phosphorylated APP (pAPP) is excluded from endosomes, and localizes to the Golgi apparatus and to transport vesicles within the neurites. Whereas the neuritic APP is phosphorylated by c-Jun NH(2)-terminal kinase through a pathway that is modulated by glycogen synthase kinase 3beta, the endosomal pAPP in degenerated CAD cells results from activation of cyclin-dependent kinase 5. Additional signaling pathways, leading to APP phosphorylation, become active during stress and mitosis. We conclude that distinct pathways of APP phosphorylation operate in proliferating, differentiating, stressed, and degenerating neurons.
淀粉样前体蛋白（APP）在苏氨酸668位点的磷酸化是一个与神经突延伸和囊泡货物顺行运输相关的正常过程。相比之下，APP磷酸化增加是阿尔茨海默病的一个病理特征。APP在唐氏综合征中过度表达，在培养细胞中，这种情况偶尔会导致APP磷酸化增加。正常与高APP条件下APP的磷酸化是否通过相似或不同的信号通路发生尚不清楚。在这里，我们使用脑干衍生神经元（CAD细胞）解决了这个问题。异位过度表达APP的CAD细胞经常表现出退化神经元的特征。我们发现，在退化细胞中，APP高度磷酸化并与早期内体共定位。相比之下，在正常CAD细胞中，磷酸化的APP（pAPP）被排除在内体之外，定位于高尔基体和神经突内的运输囊泡。神经突中的APP通过一种受糖原合酶激酶3β调节的途径被c-Jun NH（2）-末端激酶磷酸化，而退化CAD细胞中的内体pAPP是细胞周期蛋白依赖性激酶5激活的结果。导致APP磷酸化的其他信号通路在应激和有丝分裂期间变得活跃。我们得出结论，APP磷酸化的不同途径在增殖、分化、应激和退化的神经元中起作用。
