Cranial radiotherapy profoundly affects glia without inducing widespread cellular senescence

Abstract

Background: More than 70% of cancer patients who underwent cranial radiotherapy have cognitive problems, suggesting that they might undergo accelerated brain aging due to the cancer treatment. Radiotherapy is known to induce cellular senescence in tumors and in various cell types in vitro. Therefore, we hypothesized that cranial radiotherapy induces cellular senescence in the brain.

Methods: We treated male C57BL/6 mice with various dosages of (fractionated) CT-guided cranial radiotherapy. The brains were analyzed for various senescence and glial markers using immunohistochemistry, histochemistry, Cosmx SMI and RT-qPCR. To contextualize the findings regarding cranial radiotherapy in young animals and assess whether these changes parallel natural aging, we studied the brains from 77-week-old female mice, which is considered middle-aged to old representing early aging.

Results: Surprisingly, we found no increase in markers for cellular senescence in the brain after cranial radiotherapy. However, we did detect profound changes in different types of glia. In early-aged mice we again did not detect an increase in senescence markers, but we observed the same directionality in the effects on glia. These effects on glia were milder compared to those upon cranial radiotherapy.

Conclusion: Overall, cellular senescence in the healthy brain seems a rather uncommon phenomenon and not induced upon cranial radiotherapy, but profound changes in different types of glia were detected upon cranial radiotherapy.

Keywords: Radiotherapy-induced neurotoxicity; cellular senescence; cognitive impairment; glia; microglia.