Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological
features of AD include amyloid- (Abeta) deposition and hyperphosphorylated tau accumulation.
Although several clinical trials have been conducted to identify a cure for AD, no effective drug
or treatment has been identified thus far. Recently, the potential use of non-pharmacological
interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a
non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients.
However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been
established. In this study, we examined the effect of LDIR on A accumulation and A-mediated
pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR),
a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice,
an A-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure
to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term
exposure to LMDIR did not aect A accumulation in the brain, but significantly ameliorated
synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and
cerebral cortex. In addition, a direct neuroprotective eect was confirmed in SH-SY5Y neuronal
cells treated with A1–42 (2 M) after single irradiation (1 Gy). In BV-2 microglial cells exposed
to A and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory
molecules and activation of the nuclear factor-kappa B (NF-kB) pathway. These results indicate
that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro.
Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by
its neuroprotective and anti-inflammatory eects.