Activity requires soluble amyloid precursor protein α to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway
Activity requires soluble amyloid precursor protein α to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway
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DOI：
10.1111/j.1460-9568.2008.06398.x
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发表时间：
2008-09-01
影响因子：
3.4
通讯作者：
Ciccolini, Francesca
中科院分区：
文献类型：
--
作者：
Gakhar-Koppole, Nidhi;Hundeshagen, Phillip;Ciccolini, Francesca
已知活动可调节成年大脑中的神经元分化，但这一过程背后的信号传导机制仍有待确定。我们在此表明，活动需要可溶性淀粉样前体蛋白（sAPP）来促进从神经干细胞分化的年轻神经元的轴突生长。抑制sAPP分泌以及抗APP抗体都消除了去极化对轴突生长的影响，而外源性sAPPα与去极化相似，可诱导轴突伸长。去极化和sAPPα都需要激活N -甲基 - D -天冬氨酸受体（NMDAR）以及丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）的募集来诱导轴突生长。然而，去极化和sAPPα在调节这一信号级联中发挥不同的作用。去极化通过激活NMDAR以快速动力学诱导ERK磷酸化。相比之下，急性应用sAPPα不会导致ERK激活。然而，持续产生sAPPα对于去极化诱导的ERK磷酸化是必要的，这表明sAPPα通过间接机制促进MAPK/ERK的募集。此外，我们发现阻断NMDAR会下调APP表达，而去极化会增加sAPPα，这表明活动也可能通过调节细胞内APP和细胞外sAPPα的量在sAPP信号传导的上游起作用。最后，我们表明可溶性淀粉样前体样蛋白2（sAPLP2），而不是sAPLP1，在促进轴突生长方面与sAPP功能冗余，并且APP家族的可溶性成员需要膜结合的APP来促进轴突生长。总之，这些实验表明APP家族成员在活动依赖性神经元分化中具有新的作用。
It is known that activity modulates neuronal differentiation in the adult brain but the signalling mechanisms underlying this process remain to be identified. We show here that activity requires soluble amyloid precursor protein (sAPP) to enhance neurite outgrowth of young neurons differentiating from neural stem cells. Inhibition of sAPP secretion and anti-APP antibodies both abolished the effect of depolarization on neurite outgrowth, whereas exogenous sAPP alpha, similar to depolarization, induced neurite elongation. Depolarization and sAPP alpha both required active N-methyl-D-aspartic acid receptor (NMDAR) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) recruitment to induce neurite outgrowth. However, depolarization and sAPP alpha played different roles in modulating this signalling cascade. Depolarization induced ERK phosphorylation with fast kinetics via activation of NMDAR. By contrast, acute application of sAPP alpha did not lead to ERK activation. However, continuous generation of sAPP alpha was necessary for depolarization-induced ERK phosphorylation, indicating that sAPP alpha promotes MAPK/ERK recruitment by an indirect mechanism. In addition, we found that blockade of NMDAR down-regulated APP expression, whereas depolarization increased sAPP alpha, suggesting that activity may also act upstream of sAPP signalling by regulating the amount of cellular APP and extracellular sAPP alpha. Finally, we show that soluble amyloid precursor-like protein 2 (sAPLP2), but not sAPLP1, is functionally redundant to sAPP in promoting neurite outgrowth and that soluble members of the APP family require membrane-bound APP to enhance neurite outgrowth. In summary, these experiments indicate a novel role of APP family members in activity-dependent neuronal differentiation.