Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation Against Alzheimer’s Disease in 3xTg-AD Mice

Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer’s Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in an AD mouse model (3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of early-stage AD mice (3xTg-AD, 26-28 weeks age) (0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration, were analyzed in the brain of AD mice. KLDR (110 kV) significantly inhibited cognitive decline in AD mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α and IL-1β), along with marked decreases in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.