γ-Radiation Induces Long-Term Dose-Related Proteomic and Phosphorylated-Tau Species Changes in Non-Human Primate Hippocampus

Background Long-term neurological consequences of acute total-body γ-radiation are poorly understood. Here we have investigated the persistency of molecular changes in non-human primates (NHPs) more than five years after a single exposure to either a ~ 4Gy or ~ 8Gy dose. Methods MS-based proteomic analyses were performed on samples of micro-dissected hippocampus from the brains of irradiated NHPs, having received 4 or 8Gy total-body γ-radiation at least 5 years previously. Interpretation of proteomic data was subsequently expanded through STRING and DAVID analyses. Confirmation of proteomic findings was further assessed using Western blot and digital-PCR. Where applicable, data was analyzed using Student t-tests. Results Proteomic analysis of the hippocampus revealed profound, dose-dependent molecular changes. The ~ 4Gy dose primarily impacted synaptic plasticity, while the ~ 8Gy dose affected catabolism, vascular development, and inflammation. Apelin receptor (APLNR) was the only protein consistently lowered at both radiation doses, suggesting it may be a key biomarker for radiation-induced brain injury. Significantly, while most proteins linked to neurodegeneration were unchanged, Tau protein (MAPT) levels increased at the ~ 8Gy dose, and some animals developed Tau-positive lesions resembling neurofibrillary tangles. The study also found complex, dose-specific alterations in phosphorylated forms of other key proteins like alpha-synuclein and TDP-43. Conclusion Overall, the findings demonstrate that different radiation doses induce distinct and persistent molecular changes in the NHP hippocampus. This work highlights the dysregulation of proteins associated with neurodegeneration as a major long-term consequence of radiation, providing new insights into the molecular basis for post-exposure cognitive deficits.