Guglielmotto Michela, Monteleone Debora, Piras Antonio, Valsecchi Valeria, Tropiano Marta, Ariano Stefania, Fornaro Michele, Vercelli Alessandro, Puyal Julien, Arancio Ottavio, Tabaton Massimo, Tamagno Elena
Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
Department of Clinical and Biological Sciences; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
Autophagy. 2014 Oct 1;10(10):1827-43. doi: 10.4161/auto.30001. Epub 2014 Aug 12.
The role of autophagy and its relationship with apoptosis in Alzheimer disease (AD) pathogenesis is poorly understood. Disruption of autophagy leads to buildup of incompletely digested substrates, amyloid-β (Aβ) peptide accumulation in vacuoles and cell death. Aβ, in turn, has been found to affect autophagy. Thus, Aβ might be part of a loop in which it is both the substrate of altered autophagy and its cause. Given the relevance of different soluble forms of Aβ1-42 in AD, we have investigated whether monomers and oligomers of the peptide have a differential role in causing altered autophagy and cell death. Using differentiated SK-N-BE neuroblastoma cells, we found that monomers hamper the formation of the autophagic BCL2-BECN1/Beclin 1 complex and activate the MAPK8/JNK1-MAPK9/JNK2 pathway phosphorylating BCL2. Monomers also inhibit apoptosis and allow autophagy with intracellular accumulation of autophagosomes and elevation of levels of BECN1 and LC3-II, resulting in an inhibition of substrate degradation due to an inhibitory action on lysosomal activity. Oligomers, in turn, favor the formation of the BCL2-BECN1 complex favoring apoptosis. In addition, they cause a less profound increase in BECN1 and LC3-II levels than monomers without affecting the autophagic flux. Thus, data presented in this work show a link for autophagy and apoptosis with monomers and oligomers, respectively. These studies are likely to help the design of novel disease modifying therapies.
自噬在阿尔茨海默病（AD）发病机制中的作用及其与细胞凋亡的关系目前仍知之甚少。自噬功能紊乱会导致未完全消化的底物堆积、淀粉样β蛋白（Aβ）肽在液泡中积累以及细胞死亡。反过来，人们发现Aβ会影响自噬。因此，Aβ可能是一个循环的一部分，在这个循环中，它既是自噬改变的底物，也是其原因。鉴于不同可溶性形式的Aβ1-42在AD中的相关性，我们研究了该肽的单体和寡聚体在导致自噬改变和细胞死亡方面是否具有不同作用。利用分化的SK-N-BE神经母细胞瘤细胞，我们发现单体阻碍自噬性BCL2-BECN1/Beclin 1复合物的形成，并激活MAPK8/JNK1-MAPK9/JNK2途径使BCL2磷酸化。单体还抑制细胞凋亡，并允许自噬发生，导致自噬体在细胞内积累以及BECN1和LC3-II水平升高，由于对溶酶体活性的抑制作用，导致底物降解受到抑制。相反，寡聚体有利于BCL2-BECN1复合物的形成，从而促进细胞凋亡。此外，它们导致BECN1和LC3-II水平的升高程度低于单体，且不影响自噬通量。因此，这项工作中呈现的数据分别显示了自噬和细胞凋亡与单体和寡聚体之间的联系。这些研究可能有助于设计新型疾病修饰疗法。
