RESUMO
BACKGROUND: Cranial radiotherapy is standard of care for high-grade brain tumors and metastases; however, it induces debilitating neurocognitive impairments in cancer survivors, especially children. As the numbers of pediatric brain cancer survivors continue improving, the numbers of individuals developing life-long neurocognitive sequalae are consequently expected to rise. Yet, there are no established biomarkers estimating the degree of the irradiation-induced brain injury at completion of radiotherapy to predict the severity of the expected neurocognitive complications. We aimed to identify sensitive biomarkers associated with brain response to irradiation that can be measured in easily accessible clinical materials, such as liquid biopsies. METHODS: Juvenile mice were subjected to cranial irradiation with 0.5, 1, 2, 4 and 8 Gy. Cerebrospinal fluid (CSF), plasma and brains were collected at acute, subacute, and subchronic phases after irradiation, and processed for proteomic screens, molecular and histological analyses. RESULTS: We found that the levels of ectodysplasin A2 receptor (EDA2R), member of tumor necrosis factor receptor superfamily, increased significantly in the CSF after cranial irradiation, even at lower irradiation doses. The levels of EDA2R were increased globally in the brain acutely after irradiation and decreased over time. EDA2R was predominantly expressed by neurons, and the temporal dynamics of EDA2R in the brain was reflected in the plasma samples. CONCLUSIONS: We propose EDA2R as a promising potential biomarker reflecting irradiation-induced brain injury in liquid biopsies. The levels of EDA2R upon completion of radiotherapy may aid in predicting the severity of IR-induced neurocognitive sequalae at a very early stage after treatment.
RESUMO
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1- microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
