Effects of cranial X-ray irradiation in Presymptomatic 3 × Tg-AD mice

Recently, several animal studies have demonstrated the therapeutic potential of low-dose radiation therapy (LDRT) for Alzheimer's disease (AD), especially in decreasing amyloid-beta (Aβ) plaques. However, clinical concerns regarding the duration of efficacy and long-term safety of this treatment remain understudied. Additionally, LDRT has been shown to alleviate various neurological disorders. We hypothesize that the therapeutic mechanisms of LDRT in AD may extend beyond targeting Aβ and tau alone. In this study, we administered whole-brain X-ray irradiation (10 Gy in 5 fractions) to presymptomatic AD mice to re-examine its mechanism of action, duration of efficacy, and long-term safety profile.

Two months after irradiation, the autonomous activity of 3 × Tg-AD mice was significantly enhanced, with specific improvements in the spatial learning and memory in females. Western blotting revealed reduced tau phosphorylation at Ser262 site in the hippocampus of females. SnRNA-seq demonstrated restored neuronal network in females. However, these therapeutic effects appeared exhibited transient characteristics. By ten months post-irradiation, no significant behavioral and AD-related pathological changes were detected across groups, except for the elevated Aβ1-42 in the hippocampus of females.

In conclusion, the effects of early X-ray intervention on 3 × Tg-AD mice were sex-specific and time-dependent. The short-term improvement observed in female mice may be attributed to attenuated tau hyperphosphorylation and restored neuronal networks. Longitudinal observation over ten consecutive months post-irradiation showed no evidence of severe adverse effects.