The Vitamin A Derivative All-Trans Retinoic Acid Repairs Amyloid-β-Induced Double-Strand Breaks in Neural Cells and in the Murine Neocortex

Abstract

The amyloid-β peptide or Aβ is the key player in the amyloid-cascade hypothesis of Alzheimer's disease. Aβ appears to trigger cell death but also production of double-strand breaks (DSBs) in aging and Alzheimer's disease. All-trans retinoic acid (RA), a derivative of vitamin A, was already known for its neuroprotective effects against the amyloid cascade. It diminishes, for instance, the production of Aβ peptides and their oligomerisation. In the present work we investigated the possible implication of RA receptor (RAR) in repair of Aβ-induced DSBs. We demonstrated that RA, as well as RAR agonist Am80, but not AGN 193109 antagonist, repair Aβ-induced DSBs in SH-SY5Y cells and an astrocytic cell line as well as in the murine cortical tissue of young and aged mice. The nonhomologous end joining pathway and the Ataxia Telangiectasia Mutated kinase were shown to be involved in RA-mediated DSBs repair in the SH-SY5Y cells. Our data suggest that RA, besides increasing cell viability in the cortex of young and even of aged mice, might also result in targeted DNA repair of genes important for cell or synaptic maintenance. This phenomenon would remain functional up to a point when Aβ increase and RA decrease probably lead to a pathological state.

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

“…This clearly illustrates the effect of Aβ on DSB production and of the counteracting effect of RA, i.e., an effect that can either be reparative (RA added after Aβ) or protective (RA added at the same time or before Aβ). Whereas in a previous publication we demonstrated that RA can repair Aβ-induced DSBs [27], in the present work, we showed that RA also prevents Aβ-induced DSBs. RA can do it not only in SH-SY5Y and astrocytic DI TNC 1 cells but also in the neocortex of young and aged C57BL/6J mice.…”

“…Thus, by changing the expression of enzymes of the amyloid cascade, RA might also prevent the formation of Aβ-induced DSBs and be a factor of neuroprotection against Aβ-induced DSBs and not just of DSB repair. The aim of the present study was to demonstrate that indeed RA not only repairs Aβ-induced DSBs, as described in our previous publication [27], but also prevents their occurrence. For such a purpose, neuroprotective experiments have been carried out with RA added before or at the same time as Aβ and not after as in repair experiments.…”

“…In the longer term, this could also result in tilting the balance of gene expression in favor of the antiamyloidogenic pathway, via ADAM10 increased expression, thus reducing Aβ generation. We proposed previously [27] that RA is involved in the repair of Aβ-induced DSBs. We have now shown that this phenomenon appears to be complemented by RA-dependent neuroprotection.…”

“…Thus, monomeric Tau can protect DNA against heat shock-induced damages [25,26] and NAD against Aβ-induced damages [7]. Recently, we showed in astrocytic DI TNC 1 and neuroblastoma SH-SY5Y cell lines, as well as in the murine neocortex, that the vitamin A derivative all-trans-retinoic acid (RA) and the RARα/β agonist Am80 are involved in the repair of Aβ-induced DSBs [27], RA or Am80 being added after Aβ in these experiments. The DNA-dependent protein kinase (DNA-PK) of the NHEJ pathway and Ataxia Telangiectasia Mutated kinase (ATM) were shown to be implicated as repair factors [27].…”

“…Recently, we showed in astrocytic DI TNC 1 and neuroblastoma SH-SY5Y cell lines, as well as in the murine neocortex, that the vitamin A derivative all-trans-retinoic acid (RA) and the RARα/β agonist Am80 are involved in the repair of Aβ-induced DSBs [27], RA or Am80 being added after Aβ in these experiments. The DNA-dependent protein kinase (DNA-PK) of the NHEJ pathway and Ataxia Telangiectasia Mutated kinase (ATM) were shown to be implicated as repair factors [27]. This represents an additional effect of RA besides the already known ones as a neuroprotective agent for Alzheimer's disease [28][29][30][31].…”