3). In either pathway, given that NHEJ is the process involved, the importance of the DNA-PKcs/Ku complex in the development of neurodegenerative pathology may be considerable. The reduced levels of DNA-PKcs and Ku80/Ku70 subunits in post-mortem AD brains may be perceived as upstream events of neuron loss example in AD, although further studies to differentiate between cause and consequence are warranted. DNA-dependent protein kinase and amyloid beta In a recent study, sublethal levels of aggregated A??(25-35) have been shown to inhibit DNA-PK activity in nerve growth factor (NGF)-differentiated PC12 cells [82]. In this study, one of the potential mechanisms appears to be A??-induced ROS-mediated degradation of DNA-PKcs. A?? also induces DNA-PKcs carbonylation, an irreversible oxidative protein modification that may trigger its degradation by proteasomes [83,84].

DNA-PK activity is also inhibited by H2O2 in cell-free assays, indicating that ROS may directly inhibit DNA-PK activity [82]. On the other hand, A??(1-42), which can enter the nucleus of PC12 cells, also downregulates DNA-PK activity, possibly by a mechanism other than the involvement of oxidative stress. In AD cases, a decrease in DNA-PKcs expression in neurons and astrocytes, though not significant, has been reported [85]. Although it is tempting to link AD development to A??-induced attenuation of DNA-PK activity and hence to reduced NHEJ activity, it may be argued that this event is a consequence rather than the prime cause, a simultaneous event that could occur independently of A??-triggered neurotoxic pathways.

Conclusions In contrast to other NHEJ and HR factors, all three components of the DNA-PK complex (DNA-PKcs, Ku80, and Ku70) are exceptionally abundant proteins, especially in human cells [86]. Given the complexity of AD, a clear distinction is lacking as to whether the expression of DNA-PK subunits may have been transcriptionally impaired in AD brains because of a hitherto unknown upstream event that is too generic to have a specifically targeted effect on DNA-PK. As for the reduced level of DNA-PKcs, A??-induced proteasome-mediated degradation of DNA-PKcs has been proposed [83,84]. Cilengitide With regard to other NHEJ components as essential as DNA-PK (for example, Artemis), their status in AD remains unexplored. In AD, it is possible that with already-declining NHEJ activity due to the defects in some other components associated Navitoclax molecular weight with the process, a reduced DNA-PK activity may be consequential or a secondary effect. Therefore, a decline in DNA-PK subunit levels and its kinase activity may, for the time being, serve as biomarkers until future studies, especially in vivo studies, add to substantiate a direct link of DNA-PK to AD.