In this study, we have investigated the role of all-trans-retinoic acid (RA) as a neuroprotective agent against Aβ_1-42-induced DNA double-strand breaks (DSBs) in neuronal SH-SY5Y and astrocytic DI TNC₁ cell lines and in murine brain tissues, by single-cell gel electrophoresis. We showed that RA does not only repair Aβ_1-42-induced DSBs, as already known, but also prevents their occurrence. This effect is independent of that of other antioxidants studied, such as vitamin C, and appears to be mediated, at least in part, by changes in expression, not of the RARα, but of the PPARβ/δ and of antiamyloidogenic proteins, such as ADAM10, implying a decreased production of endogenous Aβ. Whereas Aβ_1-42 needs transcription and translation for DSB production, RA protects against Aβ_1-42-induced DSBs at the posttranslational level through both the RARα/β/γ and PPARβ/δ receptors as demonstrated by using specific antagonists. Furthermore, it could be shown by a proximity ligation assay that the PPARβ/δ-RXR interactions, not the RARα/β/γ-RXR interactions, increased in the cells when a 10 min RA treatment was followed by a 20 min Aβ_1-42 treatment. Thus, the PPARβ/δ receptor, known for its antiapoptotic function, might for these short-time treatments play a role in neuroprotection via PPARβ/δ-RXR heterodimerization and possibly expression of antiamyloidogenic genes. Overall, this study shows that RA can not only repair Aβ_1-42-induced DSBs but also prevent them via the RARα/β/γ and PPARβ/δ receptors. It suggests that the RA-dependent pathways belong to an anti-DSB Adaptative Gene Expression (DSB-AGE) system that can be targeted by prevention strategies to preserve memory in Alzheimer’s disease and aging.

中文翻译：

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多种视黄酸依赖性途径介导了针对淀粉样β诱导的DNA双链断裂的神经保护作用。

在这项研究中，我们已经调查清一色的作用反式作为针对甲神经保护剂-视黄酸（RA）β _1-42诱导的DNA双链断裂（DSB的）神经元SH-SY5Y和星形细胞DI TNC ₁细胞系和鼠脑组织中，通过单细胞凝胶电泳。我们发现，RA不仅修复β _1-42诱导的DNA双链断裂，因为已经知道，而且还防止其发生。这种效果是独立的，所研究的其它抗氧化剂，如维生素C，并似乎介导的，至少部分地通过在表达的变化，而不是的RAR α，但的PPAR β / δ和antiamyloidogenic蛋白质，如ADAM10，意味着减少产生内源性A的的β。而A β _1-42需要的转录和翻译为DSB生产，RA可防御β _1-42诱导的DSB的在通过两个RAR翻译后水平α / β / γ和PPAR β / δ受体所证实，通过使用特异性拮抗剂。此外，它可以由一个邻近连接测定来表明PPAR β / δ -RXR相互作用，而不是RAR α / β / γ-RXR相互作用，当10分钟RA治疗之后是20分钟A在细胞中增加β _1-42处理。因此，PPAR β / δ受体，其抗凋亡作用众所周知，可能会为这些短时治疗神经保护通过PPAR发挥作用的β / δ -RXR异二聚体，并可能antiamyloidogenic基因的表达。总体而言，这项研究表明，RA不仅可以修复β _1-42诱导的DNA双链断裂而且还可以防止他们通过RAR α / β / γ和PPAR β / δ受体。这表明RA依赖性途径属于抗DSB适应性基因表达（DSB-AGE）系统，其可以通过预防策略来靶向，以保留阿尔茨海默氏病和衰老中的记忆。