Neuroprotection against Amyloid-β-Induced DNA Double-Strand Breaks Is Mediated by Multiple Retinoic Acid-Dependent Pathways

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 TNC(1) 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.