Decipher the Role of Lipid Metabolism in Radiotherapy Induced Neurotoxicity

Jiani Xing (Advisor: Jian Hu, PhD)

While cranial radiotherapy remains an important treatment for many central nervous system tumors, its therapeutic benefit can be accompanied by persistent cognitive deficits, particularly in pediatric patients. Mechanistically, these radiation-related cognitive changes have been attributed largely to disrupted neurogenesis and inflammatory remodeling of the brain microenvironment. However, the contribution of astrocyte lipid metabolism remains poorly understood. As a major source of cholesterol support for neurons, we hypothesized that radiation disrupts astrocyte cholesterol homeostasis, which in turn leads to neurotoxicity and eventually cognitive decline.

In the current study, we combined both the in vitro system, immortalized human astrocytes (AST-1), and the in vivo fractionated whole-brain irradiation mouse model, to address this hypothesis. We observed that radiation induced early astrocyte injury, characterized by increased DNA damage, apoptosis, and GFAP activation in both models. At 1-day post-irradiation, Qki5 gene expression level was reduced, and the downstream cholesterol-related genes showed downward trends. Meanwhile, radiation led to membrane-associated cholesterol and neutral lipid accumulation, suggesting disrupted lipid homeostasis and redistribution of lipid pools in astrocytes. Interestingly, exogenous cholesterol supplementation partially rescued radiation-induced astrocyte loss, suggesting the potential protective role of cholesterol in radiation injuries. At late-stage post-radiation treatment, irradiated mice exhibited alopecia and behavioral changes.

Together, these findings suggest that radiation may disrupt astrocyte cholesterol homeostasis in the QKI dependent manner, which could contribute to neurotoxicity and later cognitive dysfunction.

Advisory Committee:

• Jian Hu, PhD, Chair
• Joseph Duman, PhD
• David Grosshans, MD, PhD
• Jiaqian Wu, PhD
• Hongyuan Yang, PhD