Glioblastoma and its treatment are associated with extensive accelerated brain aging.

Progressive neurocognitive dysfunction is the leading cause of a reduced quality of life in patients with primary brain tumors. Understanding how the human brain responds to cancer and its treatment is essential to improve the associated cognitive sequelae. In this study, we performed integrated transcriptomic and tissue analysis on postmortem normal-appearing non-tumor brain tissue from glioblastoma (GBM) patients that had received cancer treatments, region-matched brain tissue from unaffected control individuals and Alzheimer's disease (AD) patients. We show that normal-appearing non-tumor brain regions of patients with GBM display hallmarks of accelerated aging, in particular mitochondrial dysfunction, inflammation, and proteostasis deregulation. The extent and spatial pattern of this response decreased with distance from the tumor. Gene set enrichment analyses and a direct comparative analysis with an independent cohort of brain tissue samples from AD patients revealed a significant overlap in differentially expressed genes and a similar biological aging trajectory. Additionally, these responses were validated at the protein level showing the presence of increased lysosomal lipofuscin, phosphorylated microtubule-associated protein Tau, and oxidative DNA damage in normal-appearing brain areas of GBM patients. Overall, our data show that the brain of GBM patients undergoes accelerated aging and shared AD-like features, providing the basis for novel or repurposed therapeutic targets for managing brain tumor-related side effects.

Radiotherapy induces persistent innate immune reprogramming of microglia into a primed state.

Over half of patients with brain tumors experience debilitating and often progressive cognitive decline after radiotherapy treatment. Microglia, the resident macrophages in the brain, have been implicated in this decline. In response to various insults, microglia can develop innate immune memory (IIM), which can either enhance (priming or training) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigate whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats show a stronger immune response to a secondary inflammatory insult, demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of postmortem normal-appearing non-tumor brain tissue of patients with glioblastoma indicates that radiation-induced microglial priming is likely conserved in humans. Targeting microglial priming or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity.

Proton therapy induces a local microglial neuroimmune response.

BACKGROUND AND PURPOSE: Although proton therapy is increasingly being used in the treatment of paediatric and adult brain tumours, there are still uncertainties surrounding the biological effect of protons on the normal brain. Microglia, the brain-resident macrophages, have been shown to play a role in the development of radiation-induced neurotoxicity. However, their molecular and hence functional response to proton irradiation remains unknown. This study investigates the effect of protons on microglia by comparing the effect of photons and protons as well as the influence of age and different irradiated volumes. MATERIALS AND METHODS: Rats were irradiated with 14 Gy to the whole brain with photons (X-rays), plateau protons, spread-out Bragg peak (SOBP) protons or to 50 % anterior, or 50 % posterior brain sub-volumes with plateau protons. RNA sequencing, validation of microglial priming gene expression using qPCR and high-content imaging analysis of microglial morphology were performed in the cortex at 12 weeks post irradiation. RESULTS: Photons and plateau protons induced a shared transcriptomic response associated with neuroinflammation. This response was associated with a similar microglial priming gene expression signature and distribution of microglial morphologies. Expression of the priming gene signature was less pronounced in juvenile rats compared to adults and slightly increased in rats irradiated with SOBP protons. High-precision partial brain irradiation with protons induced a local microglial priming response and morphological changes. CONCLUSION: Overall, our data indicate that the brain responds in a similar manner to photons and plateau protons with a shared local upregulation of microglial priming-associated genes, potentially enhancing the immune response to subsequent inflammatory challenges.