Carbon-12 and Gamma-Rays Combined Irradiation Ameliorates Behavioral and Biochemical Alterations in Tau P301S Homozygous Transgenic Mice.

No effective treatments currently exist for tauopathies. Given emerging evidence that moderate-dose ionizing radiation (IR) may exert neuroreparative effects in neurodegeneration, we investigated the impact of combined IR exposure on disease progression in the Tau P301S mouse model. Tau P301S mice received combined gamma-ray (0.24 Gy) and carbon-12 nuclei (0.18 Gy, 400 MeV/n) irradiation at the presymptomatic stage. Following longitudinal behavioral testing until the terminal stage, post-mortem brains were analyzed via RT-qPCR, ELISA, and HPLC to assess gene expression, protein levels, and monoamine quantification. At the symptomatic stage, Tau+R mice showed normalized endurance, fear-dependent memory, and disinhibition-like behavior, reaching wild-type levels. At the terminal stage, Tau+R mice demonstrated significantly superior balance, coordination, and grip strength compared to untreated Tau P301S mice. These benefits correlated with restored striatal serotonin and a 76% reduction in cerebellar tau protein (transcription-independent). Furthermore, IR normalized Gsk3b expression in the hippocampus and cerebellum, and Trem2 in the cerebellum, to WT levels. Notably, IR up-regulated cerebellar Iba1 by 31% and 86% compared to WT and Tau mice, respectively. Combined radiotherapy not only alleviates behavioral symptoms but also modulates key neurochemical parameters. These findings demonstrate robust symptomatic improvements and suggest a potential neuroprotective capacity of combined radiotherapy in a mouse model of severe tauopathy.