The role of secreted APP in modulation of the Akt survival signaling pathway and neuroprotection

淀粉样前体蛋白及其各种裂解产物的生理作用迄今尚未完全了解，但越来越多的证据表明，APP功能的丧失是脑老化过程中神经元可塑性降低、突触信号传导减少和神经元对细胞应激敏感性增强的基础。我们实验室之前的研究表明，sAPPalpha是通过α-分泌酶的活性沿着分泌途径切割APP而产生的，它通过调节基因表达以及拮抗神经毒性应激条件来发挥有效的神经保护作用，从而抑制应激触发的细胞死亡。在我们最近未发表的工作中，我们还可以证明sAPPa是Akt存活信号通路的关键激活剂，APP而不是APLP 1和APLP 2特异性地作为sAPPa介导的神经保护的受体/辅助受体发挥作用。这些令人兴奋的新发现为在拟议项目中对sAPP α介导的神经保护进行详细的分子分析提供了坚实的基础。特别是，我们将专注于APP功能结构域和假定的共同受体所需的细胞内转导的sAPP α介导的生存信号，并在相关的sAPP α下游目标介导的神经保护。

The physiological roles of the amyloid precursor protein and its various cleavage products are hitherto not fully understood, but accumulating evidence suggests that loss of APP function underlies reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. Previous studies from our lab suggest that sAPPalpha which is generated via cleavage of APP by the activity of alpha-secretase along the secretory pathway exerts potent neuroprotective effects via modulation of gene expression as well as by antagonizing neurotoxic stress conditions, thereby inhibiting stress-triggered cell death. In our most recent unpublished work, we could also demonstrate that sAPPalpha is a key activator of the Akt survival signaling pathway and that APP, but not APLP1 and APLP2 specifically functions as a receptor/co-receptor for sAPPalpha-mediated neuroprotection. These exciting novel findings provide a solid basis for a detailed molecular analysis of sAPPalpha-mediated neuroprotection in the proposed project. In particular, we will focus on APP functional domains and putative co-receptors required for intracellular transduction of sAPPalpha-mediated survival signaling, and on the relevant sAPPalpha downstream targets mediating neuroprotection.