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

Published inNeural Plasticity, vol. 2020, no. 9369815
Publication date2020
Abstract

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.

Keywords
  • 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
Citation (ISO format)
COLAS, Julien et al. Neuroprotection Against Amyloid-b Induced DNA Double-Strand Breaks is Mediated by Multiple Retinoic Acid-Dependent Pathways. In: Neural Plasticity, 2020, vol. 2020, n° 9369815. doi: 10.1155/2020/9369815
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Article (Published version)
Identifiers
ISSN of the journal2090-5904
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Creation04/15/2020 10:08:00 AM
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