Schaefer Patrick M, von Einem Bjoern, Walther Paul, Calzia Enrico, von Arnim Christine A F
Institute of Neurology, Ulm University, Ulm, Germany.
Central Facility for Electron Microscopy, Ulm University, Ulm, Germany.
PLoS One. 2016 Dec 22;11(12):e0168157. doi: 10.1371/journal.pone.0168157. eCollection 2016.
One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.
阿尔茨海默病的一个标志是由淀粉样蛋白β（Aβ）组成的老年斑，Aβ由淀粉样前体蛋白（APP）加工而来。线粒体功能障碍与阿尔茨海默病的发病机制有关，并且在分离系统中，Aβ和APP均被报道会影响线粒体功能。然而，在完整细胞中，考虑到APP和Aβ的生理定位，引发线粒体缺陷的因素尚待明确。因此，本研究的目的是就APP和Aβ的亚细胞定位，剖析它们在诱导线粒体改变方面的影响。我们分别过表达了APP或β-位点淀粉样前体蛋白裂解酶1（BACE1），从而分别提高APP和Aβ水平或仅提高Aβ水平。通过全面的代谢特征分析，我们证明，尽管与BACE过表达相比细胞外Aβ水平较低，但只有APP过表达会降低线粒体呼吸。令人惊讶的是，这可以被γ-分泌酶抑制剂挽救，这反而表明存在Aβ介导的线粒体毒性。对Aβ定位的分析表明，细胞内Aβ水平以及APP/Aβ与线粒体空间关联的增加与线粒体呼吸降低有关。因此，我们的数据为细胞内Aβ积累在阿尔茨海默病相关线粒体功能障碍中起重要作用提供了显著证据。由此突出了APP加工和细胞内运输的定位作为线粒体功能的决定性因素的重要性，将神经退行性疾病的两个主要标志联系起来。
