Abstract
Recently, we showed that DNA double-strand breaks (DSBs) are increased by the Aβ42-amyloid peptide and decreased by all-trans retinoic acid (RA) in SH-SY5Y cells and C57BL/6J mice. The present work was aimed at investigating DSBs in cells and murine models of Alzheimer's disease carrying the preseniline-1 (PS1) P117L mutation. We observed that DSBs could hardly decrease following RA treatment in the mutated cells compared to the wild-type cells. The activation of the amyloidogenic pathway is proposed in the former case as Aβ42- and RA-dependent DSBs changes were reproduced by an α-secretase and a γ-secretase inhibitions, respectively. Unexpectedly, the PS1 P117L cells showed lower DSB levels than the controls. As the DSB repair proteins Tip60 and Fe65 were less expressed in the mutated cell nuclei, they do not appear to contribute to this difference. On the contrary, full-length BRCA1 and BARD1 proteins were significantly increased in the chromatin compartment of the mutated cells, suggesting that they decrease DSBs in the pathological situation. These Western blot data were corroborated by in situ proximity ligation assays: the numbers of BRCA1-BARD1, not of Fe65-Tip60 heterodimers, were increased only in the mutated cell nuclei. RA also enhanced the expression of BARD1 and of the 90 kDa BRCA1 isoform. The increased BRCA1 expression in the mutated cells can be related to the enhanced difficulty to inhibit this pathway by BRCA1 siRNA in these cells. Overall, our study suggests that at earlier stages of the disease, similarly to PS1 P117L cells, a compensatory mechanism exists that decreases DSB levels via an activation of the BRCA1/BARD1 pathway. This supports the importance of this pathway in neuroprotection against Alzheimer's disease.
Highlights
The presenilin-1 (PS1) P117L mutation is associated with one of the most severe forms of early-onset familial Alzheimer’s disease (AD), with one patient deceased at the age of 28 y [1]
As the activation of the amyloidogenic cascade in the Mut clones should result in increased double-strand breaks (DSBs), we investigated whether the PS1 P117L mutation might favor, in parallel to the increase of Aβ42, the translocation of Tip60/Fe65 proteins in the nucleus to repair the DSBs
Our data shows that the PS1 P117L mutation is responsible for a decreased efficiency of retinoic acid (RA)-dependent DSB repair
Summary
The presenilin-1 (PS1) P117L mutation is associated with one of the most severe forms of early-onset familial Alzheimer’s disease (AD), with one patient deceased at the age of 28 y [1]. In the SH-SY5Y cells, the PS1 P117L mutation did not alter the cellular morphology consistently [3], and when treated with all-trans retinoic acid (RA), these mutated cells differentiated normally [4] but potentiated the cell cycle arrest in the G1 phase [5]. In progenitor cells originating from embryos of PS1 P117L mice, Neural Plasticity we observed only faint impairments of cell differentiation [6]. The PS1 P117L mice overproduced Aβ42, and not Aβ40 [7], but developed only few plaques and virtually no neurofibrillary tangles [9] This mutation contributes to disinhibitory tendencies and a lower ability of mice to adapt to novel environments [9]. This ressembles the disoriented behavior of the PS1 P117L AD patients
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