Modulation of Neuroinflammation by Low-dose Radiation Therapy in an Animal Model of Alzheimer's Disease

Background

Recently, several studies have reported that low dose radiation therapy (RT) reduces the release of pro-inflammatory cytokines in inflammatory-degenerative disorders including Alzheimer's disease (AD). AD is the most common cause of dementia, and neuroinflammation is one of the major contributing factors in AD pathogenesis. Thus, low dose RT is expected to be used clinically for treating AD. However, the proper doses, effects, and underlying mechanisms of RT in AD have not been determined. Therefore, in this study, we aimed to determine the appropriate RT dose and schedule for AD treatment, and to investigate the therapeutic effects and mechanisms of low-dose RT in AD.

Methods

We first determined the proper dose and schedule of RT in late stage AD using 8–9-month old 5x familial AD(5xFAD) mice, a well-known animal model of AD, by comparing the effects of a low total dose with a low dose per fraction (LD-LDRT, 5 × 0.6 Gy) and a low-moderate total dose with a conventional dose per fraction (LMD-CDRT, 5 × 2 Gy).

Results

LD-LDRT and LMD-CDRT were found to reduce the level of pro-inflammatory cytokines, i.e. CD54, IL-3, CXCL9/10, and CCL2/4 in the hippocampus of 5xFAD mice. Further, increased microgliosis assessed with Iba-1 was significantly reduced by LD-LDRT in the hippocampus of 5xFAD mice. Moreover, LD-LDRT and LMD-CDRT decreased the amyloid plaque burden in 5xFAD mice and attenuated their cognitive impairment; these effects persisted for nearly one month.

Conclusions

The present study showed that LD-LDRT rescues cognitive impairment and prevents accumulation of amyloid plaques by regulating neuroinflammation in the late stage of AD, with an efficacy equivalent to that of LMD-CDRT. Furthermore, it suggests that LD-LDRT may facilitate accessible and convenient treatment in clinical trials compared to LMD-CDRT.