Gilson Virginie, Mbebi-Liegeois Corinne, Sellal François, de Barry Jean
Institut des Neurosciences Cellulaires et Intégratives-CNRS, Strasbourg, France.
Universitéde Strasbourg, Strasbourg, France.
J Alzheimers Dis. 2015;47(2):453-66. doi: 10.3233/JAD-142529.
Numerous studies have shown that amyloid-β (Aβ) modulate intracellular metabolic cascades and an intracellular Ca2+ homeostasis and a cell surface NMDA receptor expression alteration in Alzheimer's disease (AD). However most of these findings have been obtained by using non-physiological Aβ concentrations. The present study deals with the effect of low Aβ concentrations on cellular homeostasis. We used nerve growth factor-differentiated PC12 cells and murine cortical neurons sequentially treated with low chronic monomeric or small oligomeric Aβ concentrations and high acute oligomeric Aβ concentrations to bring out a priming effect of chronic treatment on subsequently high Aβ concentrations-elicited cellular response. Both cell types indeed displayed an enhanced capacity to bind oligomeric Aβ after monomeric or small oligomeric Aβ application. Furthermore, the results show that monomeric Aβ1-42 application to the cells induces an increase of the Ca2+-response and of the membrane expression of the extrasynaptic subunit of the NMDA receptor GluN2B in PC12 cells, while the opposite effects were observed in cultured neurons. This suggests a sequential interaction of Aβ with the cellular plasma membrane involving monomers or small Aβ oligomers which would facilitate the binding of the deleterious high molecular Aβ oligomers. This mechanism would explain the slow progression of AD in the human nervous system and the deep gradient of neuronal death observed around the amyloid plaques in the nervous tissue.
大量研究表明，在阿尔茨海默病（AD）中，β淀粉样蛋白（Aβ）可调节细胞内代谢级联反应、细胞内钙离子稳态以及细胞表面N-甲基-D-天冬氨酸（NMDA）受体表达变化。然而，这些发现大多是通过使用非生理性Aβ浓度获得的。本研究探讨低浓度Aβ对细胞内稳态的影响。我们使用经神经生长因子分化的PC12细胞和小鼠皮质神经元，先用低浓度慢性单体或小寡聚体Aβ处理，再用高浓度急性寡聚体Aβ处理，以揭示慢性处理对随后高浓度Aβ引发的细胞反应的启动作用。在应用单体或小寡聚体Aβ后，这两种细胞类型确实都表现出结合寡聚体Aβ的能力增强。此外，结果表明，在PC12细胞中应用单体Aβ1-42可诱导钙离子反应增加以及NMDA受体GluN2B胞外亚基的膜表达增加，而在培养的神经元中观察到相反的效果。这表明Aβ与细胞质膜存在顺序性相互作用，涉及单体或小Aβ寡聚体，这将促进有害高分子量Aβ寡聚体的结合。这种机制可以解释AD在人类神经系统中的缓慢进展以及在神经组织淀粉样斑块周围观察到的神经元死亡深度梯度。
