Neuroprotection Against Amyloid-b Induced DNA Double-Strand Breaks is Mediated by Multiple Retinoic Acid-Dependent Pathways

Article Article scientifique Article Neuroprotection Against Amyloid-b Induced DNA Double-Strand Breaks is Mediated by Multiple Retinoic Acid-Dependent Pathways eng 2020 author Colas Julien 844025 author Chessel Natacha 675416 author Ouared Ahmed Allaeddine 839799 author Gruz-Gibelli Da Mouta Emmanuelle 674491 author Marin Pascale 22116 author Herrmann François 70980 author Savioz Armand 0000-0001-8059-8281 135243 10.1155/2020/9369815 32256561 2090-5904 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109576/ 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. A-Tocopherol Ab peptide Aging Alzheimer's disease Cell viability Cerebral cortex Cortical layers Double strand breaks Glutathione L-carnosine Okadaic acid PPAR RAR Retinoic acid Secretase SH-SY5Y Vitamin C Dewey 590 Dewey 616.8 Dewey 616.89 Dewey 618.97 16 Centre interfacultaire de neurosciences 0D9 44 Département de génétique et évolution 162 60 Département de psychiatrie 225 65 Département de réadaptation et gériatrie 22B false 1221 Neuroimagerie moléculaire en psychiatrie 983 Neural Plasticity 2020 9369815 0caa111d-afee-4110-9774-1e1c00dcea4a Article (Published version) Public Colasetal.pdf 2351285 application/pdf CC BY openAccess Centres et instituts / Centre interfacultaire de neurosciences Faculté des sciences / Section de biologie / Département de génétique et évolution Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de médecine / Section de médecine clinique / Département de réadaptation et gériatrie

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Neuroprotection Against Amyloid-b Induced DNA Double-Strand Breaks is Mediated by Multiple Retinoic Acid-Dependent Pathways	Neural Plasticity			2020	374	154

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Ouared, Ahmed Allaeddine