Low-dose radiotherapy ameliorates Alzheimer's-like pathology in 5xFAD mice and is associated with HIF-1α-related inflammatory signaling downregulation.

Background

Whether fractionated low-dose radiotherapy (LDRT) alleviates Alzheimer's disease-like pathology and whether these effects are associated with microglial HIF-1α-related signaling remain unclear.

Methods

Male 5xFAD mice received whole-brain irradiation at 2 Gy per fraction for 5 fractions (total dose, 10 Gy). One month later, cognition was assessed by the Morris water maze and novel object recognition tests, and brain pathology was evaluated by immunofluorescence and Western blot. LPS-stimulated BV2 cells were used as an in vitro model to examine the effects of LDRT on nitric oxide, cytokines, and reactive oxygen species. Transcriptomic analysis was performed with 3 biological replicates per group, followed by pharmacological validation using the HIF-1α inhibitor YC-1.

Results

LDRT improved spatial and recognition memory, reduced Aβ plaque burden in the hippocampus and cortex, and attenuated microglial activation in 5xFAD mice. In particular, LDRT decreased the hippocampal Aβ plaque area fraction (P = 0.0065) and reduced HIF-1α expression in Iba1-positive microglia in the hippocampus (P = 0.0077). In addition, LDRT reduced Iba1 expression and CD68-positive area while preserving Aβ phagocytosis by primary microglia. In BV2 cells, LDRT inhibited LPS-induced inflammatory responses and altered 123 differentially expressed genes enriched in the HIF-1, IL-17, TNF, MAPK, and p53 signaling pathways. Pharmacological inhibition of HIF-1α by YC-1 recapitulated, but did not further enhance, the anti-inflammatory effects of LDRT.

Conclusions

Fractionated whole-brain LDRT ameliorates cognitive deficits and Aβ pathology in 5xFAD mice, with effects associated with downregulation of microglial HIF-1α-related signaling.