In this study we have investigated the role of all-trans retinoic acid (RA) as neuroprotective agent against Ab1-42-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 Ab1-42-induced DSBs, as already known, but that it also prevents their occurrence. This effect is independent of that of other anti-oxidants studied, such as vitamin C, and appears to be mediated, at least in part, by changes in expression, not of the RARa but of the PPARb/g and of anti-amyloidogenic proteins, such as ADAM10, implying a decreased production of endogenous Ab. Whereas Ab1-42 needs transcription and translation for DSBs production, RA protects against Ab1-42-induced DSBs at the post-translational level through both, the RARa/b/g and the PPARb/d receptors as demonstrated by using specific antagonists. Furthermore, it could be shown by Proximity Ligation Assay that the PPARb/d-RXR interactions, not the RARa/b/g-RXR interactions, increased in the cells when a 10 min RA treatment was followed by a 20 min Ab1-42 treatment. Thus, the PPARb/d receptor, known for its anti-apoptotic function, might for these short-time treatments play a role in neuroprotection via PPARb/d-RXR heterodimerization and possibly expression of anti-amyloidogenic genes. Overall, this study shows that RA can, not only repair Ab1-42-induced DSBs, but also prevent them via the RARa/b/g and the PPARb/d receptors. It suggests that the RA-dependent pathways belong to an anti-DSBs Adaptative Gene Expression (DSB-AGE) system that can be targeted by prevention strategies to preserve memory in Alzheimer's disease and aging.