The role of Atg7-mediated autophagy in ionizing radiation-induced neural stem cell damage.

Impairment of neurogenesis is thought to be one of the important mechanisms underlying radiation-induced cognitive decline. Self-renewal and differentiation of neural stem cells (NSCs) are important components of neurogenesis. It has been well established that autophagy plays an important role in neurodegenerative conditions, however, its role in radiation-induced cognitive decline remains unclear. Our previous studies have found that ionizing radiation (IR) induces autophagy in mouse neurons, and minocycline, an antibiotic that can cross the blood-brain barrier, protects neurons from radiation-induced apoptosis through promoting autophagy, thus may contribute to the improvement of mouse cognitive performance after whole-brain irradiation. In the present study, we investigated whether autophagy is involved in radiation-induced damage in self-renewal and differentiation of NSCs. We found that NSCs were extremely sensitive to IR. Irradiation induced autophagy in NSCs in a dose-dependent manner. Atg7 knockdown significantly decreased autophagy, thus increased the apoptosis levels in irradiated NSCs, suggesting that autophagy protected NSCs from radiation-induced apoptosis. Moreover, compared with the negative control NSCs, the neurosphere size was significantly reduced and the neuronal differentiation was notably inhibited in Atg7-deficient NSCs after irradiation, indicating that autophagy defect could exacerbate radiation-induced reduction in NSC self-renewal and differentiation potential. In conclusion, down-regulating autophagy by selective Atg7 knockdown in NSCs enhanced radiation-induced NSC damage, suggesting an important protective role of autophagy in maintaining neurogenesis. Along with the protective effect of autophagy on irradiated neurons, our results on NSCs not only shed the light on the involvement of autophagy in the development of radiation-induced cognitive decline, but also provided a potential target for preventing cognitive impairment after cranial radiation exposure.

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