DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer's Disease.

Abstract

Background:Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer’s disease (AD).Objective:To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation.Methods:We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 and Aβ42. Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology.Results:We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons.Conclusion:These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD.