Sturchler Emmanuel, Galichet Arnaud, Weibel Mirjam, Leclerc Estelle, Heizmann Claus W
Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zurich, 8032 Zurich, Switzerland.
J Neurosci. 2008 May 14;28(20):5149-58. doi: 10.1523/JNEUROSCI.4878-07.2008.
In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-beta peptide (Abeta) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that Abeta had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric Abeta species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. The receptor for advanced glycation end products (RAGE), a member of the Ig superfamily, is a cellular binding site for Abeta. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized Abeta conformations: Abeta oligomers (AbetaOs), Abeta fibrils (AbetaFs), and Abeta aggregates (AbetaAs). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either AbetaOs or AbetaAs but does not affect AbetaF toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V(d) domain of RAGE attenuates AbetaO-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of AbetaA-induced apoptosis requires the neutralization of the C(1d) domain of the receptor. Thus, our data indicate that distinct regions of RAGE are involved in Abeta-induced cellular and neuronal toxicity with respect to the Abeta aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.
在阿尔茨海默病（AD）的发病过程中，越来越多的证据表明β淀粉样肽（Aβ）引发了导致神经元丧失的致病级联反应。长期以来，人们一直认为Aβ必须组装成细胞外淀粉样纤维或聚集体才能发挥其细胞毒性作用。在过去十年中，对AD患者大脑和转基因模型中可溶性寡聚Aβ物种的表征提出了一种可能性，即Aβ的不同构象可能通过不同机制导致AD病理。晚期糖基化终产物受体（RAGE）是免疫球蛋白超家族的成员，是Aβ的细胞结合位点。在此，我们研究RAGE在由特征明确的不同Aβ构象：Aβ寡聚体（AβOs）、Aβ纤维（AβFs）和Aβ聚集体（AβAs）诱导的细胞凋亡中的作用。在我们的体外系统中，用多克隆抗RAGE抗体处理可显著提高暴露于AβOs或AβAs的SHSY-5Y细胞和神经元的存活率，但不影响AβF的毒性。有趣的是，使用位点特异性抗体，我们证明靶向RAGE的V（d）结构域可减弱AβO在SHSY-5Y细胞和大鼠皮质神经元中诱导的毒性，而抑制AβA诱导的细胞凋亡则需要中和受体的C（1d）结构域。因此，我们的数据表明，就Aβ聚集状态而言，RAGE的不同区域参与了Aβ诱导的细胞和神经元毒性，并且它们提示阻断受体的特定位点作为减轻神经元死亡的潜在治疗策略。
