Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany.
Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany.
Mol Neurobiol. 2016 Nov;53(9):5985-5994. doi: 10.1007/s12035-015-9501-y. Epub 2015 Nov 2.
Maintenance of intracellular proteostasis is essential for neuronal function, and emerging data support the view that disturbed proteostasis plays an important role in brain aging and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease (AD). sAPPalpha (sAPPα), the extracellularly secreted N-terminal alpha secretase cleavage product of the amyloid precursor protein (APP), has an established function in neuroprotection. Recently, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPα to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPPα directly affects proteostasis. Here, we demonstrate that in addition to its anti-apoptotic function, sAPPα has effects on neuronal proteostasis under conditions of proteasomal stress. In particular, recombinant sAPPα significantly suppressed MG132-triggered expression of the co-chaperone BAG3 and aggresome formation, and it partially rescued proteasomal activity in a dose-dependent manner in SH-SY5Y neuroblastoma cells. In analogy, sAPPα was able to inhibit MG132-induced BAG3 expression in primary hippocampal neurons. Strikingly, these sAPPα-induced changes were unaltered in APP-depleted SH-SY5Y cells and APP-deficient neurons, demonstrating that holo-APP is not required for this particular function of sAPPα. Importantly, recombinant sAPPbeta (sAPPβ) failed to modulate BAG3 expression and proteostasis in APP-proficient wild-type (wt) cells, indicating that these biological effects are highly selective for sAPPα. In conclusion, we demonstrate that modulation of proteostasis is a distinct biological function of sAPPα and does not require surface-bound holo-APP. Our data shed new light on the physiological functions of APP and the interplay between APP processing and proteostasis during brain aging.
维持细胞内蛋白质平衡对于神经元功能至关重要，新出现的数据支持这样一种观点，即蛋白质平衡失调在大脑衰老和与年龄相关的神经退行性疾病（如阿尔茨海默病）的发病机制中起着重要作用。sAPPα（sAPPα）是淀粉样前体蛋白（APP）的细胞外分泌的 N 端α分泌酶切割产物，具有明确的神经保护功能。最近，我们提供的证据表明，膜结合的完整 APP 与 sAPPα 共同发挥功能，通过激活 Akt 存活信号通路介导神经保护，并且 sAPPα 直接影响蛋白质平衡。在这里，我们证明了 sAPPα 除了具有抗凋亡功能外，在蛋白酶体应激条件下还对神经元蛋白质平衡有影响。特别是，重组 sAPPα 显著抑制了 MG132 触发的伴侣蛋白 BAG3 的表达和聚集体形成，并以剂量依赖的方式部分挽救了 SH-SY5Y 神经母细胞瘤细胞中的蛋白酶体活性。类似地，sAPPα 能够抑制 MG132 诱导的原代海马神经元中 BAG3 的表达。引人注目的是，在 APP 耗尽的 SH-SY5Y 细胞和 APP 缺陷神经元中，这些 sAPPα 诱导的变化没有改变，这表明完整的 APP 对于 sAPPα 的这一特定功能不是必需的。重要的是，重组 sAPPβ（sAPPβ）未能调节 APP 功能正常的野生型（wt）细胞中的 BAG3 表达和蛋白质平衡，这表明这些生物学效应对 sAPPα 具有高度选择性。总之，我们证明了蛋白质平衡的调节是 sAPPα 的一个独特的生物学功能，不需要表面结合的完整 APP。我们的数据为 APP 的生理功能以及大脑衰老过程中 APP 处理与蛋白质平衡之间的相互作用提供了新的认识。
