Effects of damaged astrocytes on DNA damage and repair in human neurons: Implications for Alzheimer's disease

Background Studies suggest a strong association between astrocytes, neuronal DNA damage, elevated amyloid-β, and brain degeneration in Alzheimer's disease (AD). Objective This study aimed to show whether astrocytes with damaged DNA affect human neuronal progenitor cells (NPCs) or differentiated neurons in close proximity, dependent on astrocytic APOE allele expression. Methods Immortalized human astrocytes (hTERT) expressing APOE were treated with etoposide to induce DNA damage and co-cultured in a transwell system with human NPCs or differentiated neurons. We used western blotting and immunostaining to evaluate the DNA damage response of the NPCs and neurons. Results Undamaged NPCs showed increased DNA damage when co-cultured with damaged astrocytes. The astrocytic APOE genotype had little to no effect on the transcellular damage response. NPCs overexpressing the amyloid-β protein precursor responded more robustly when co-cultured with damaged astrocytes. Differentiated neurons showed no significant changes in their DNA damage response to damaged astrocytes. Conclusions This study is the first to demonstrate that astrocytic DNA damage may contribute to early stages of neuronal pathology in AD by inducing a DNA damage response in vulnerable neuronal populations.