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

分泌型 APP 在 Akt 生存信号通路调节和神经保护中的作用

基本信息

批准号：
258499424
负责人：
Professor Dr. Donat Kögel
金额：
--
依托单位：
Abteilung Experimentelle Neurochirurgie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/258499424?language=en
关键词：
role secreted APP modulation Akt

项目摘要

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 In our most recent unpublished work, we could also demonstrate that sAPPalpha is a key activator of the Akt survival signaling pathway and that APP, but not APLP1 and APLP2 specifically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.

迄今为止，淀粉样蛋白前体蛋白及其各种裂解产物的生理作用尚不完全清楚，但越来越多的证据表明，APP功能的丧失是大脑衰老过程中神经元可塑性降低、突触信号减弱和神经元对细胞应激易感性增强的基础。我们实验室之前的研究表明，sAPPalpha是通过α -分泌酶活性沿分泌途径裂解APP产生的，通过调节基因表达和拮抗神经毒性应激条件，从而抑制应激引发的细胞死亡，具有强大的神经保护作用。在我们最近未发表的工作中，我们也可以证明sAPPalpha是Akt存活信号通路的关键激活因子，并且APP，而不是APLP1和APLP2特异性地作为sAPPalpha介导的神经保护的受体/共受体。这些令人兴奋的新发现为该项目中sappalpha介导的神经保护的详细分子分析提供了坚实的基础。特别是，我们将重点关注APP功能域和sAPPalpha介导的存活信号在细胞内转导所需的推定共受体，以及介导神经保护的相关sAPPalpha下游靶点。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP

sAPPα 调节 BAG3 表达和蛋白酶体活性不需要膜束缚的 Holo-APP

DOI：
10.1007/s12035-015-9501-y
发表时间：
2017
期刊：
Molecular Neurobiology
影响因子：
5.1
作者：
Kundu A;Milosch N;Antonietti P;Baumkötter F;Zymny A;Müller UC;Kins S;Hajieva P;Behl C;Kögel D
通讯作者：
Kögel D

Role of APP Interactions with Heterotrimeric G Proteins: Physiological Functions and Pathological Consequences.

应用与异三聚体G蛋白相互作用的作用：生理功能和病理后果。