γ-Radiation induces long-term dose-related proteomic and phosphorylated-tau species changes in non-human primate...

Long-term neurological consequences of acute total-body γ-radiation are poorly understood. Here we investigated the persistency of molecular changes in non-human primates (NHPs) 5+ years after single exposure to ~4 Gy or ~8 Gy total body irradiation dose. MS-based proteomic analyses were performed on samples of micro-dissected hippocampus from brains of irradiated/control NHPs. We used STRING and DAVID analyses to expand interpretation of proteomic data. Proteomic findings were further assessed using Western blot and digital-PCR. Proteomic analysis of the hippocampus revealed profound, dose-dependent molecular changes. ~4 Gy primarily impacted synaptic plasticity, while ~8 Gy 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 (MAPT) protein levels increased at ~8 Gy, and some animals developed Tau-positive lesions resembling neurofibrillary tangles. Moreover, we found complex, dose-specific alterations in phosphorylated forms of other key proteins (alpha-synuclein, TDP-43). Overall, these findings show that different radiation doses induce distinct, persistent molecular changes in NHP hippocampus. This work highlights dysregulation of proteins usually associated with neurodegeneration (i.e., Tau and synaptic proteins) as a major long-term consequence of radiation, providing new insights into the molecular shift that accompany post-exposure high-dose radiation and likely a possible cause of post-exposure cognitive deficits.