Low-Dose Ionizing Radiation Modulates Microglia Phenotypes in the Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aβ deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aβ pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aβ deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aβ accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aβ-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aβ deposition and memory loss.

Treatment by Low-Dose Brain Radiation Therapy Improves Memory Performances without Changes of the Amyloid Load in the TgF344-AD Rat Model.

“…A positive effect of LD-RT on amyloid load was previously reported in patients presenting peripheral amyloidosis [30][31][32][33][34][35][36] and recently in three AD mouse models [15][16][17]. Nevertheless, this reduction of the number of amyloid plaques was not observed in our rat model.…”

“…Another hypothesis is the importance of the delay post treatment. Indeed, in the publications mentioned above, the maximal delay post RT analyzed is 8 weeks [15][16][17]. Thus, it is possible that 4 months post RT, as in our study, the bene cial effect of LD-RT on the amyloid is caught up by the disease progression.…”

“…In a third model, no effect on amyloid was observed 4 days post RT but LD-RT did reduce microglial activation and improved synaptic protein levels, suggesting that LD-RT protected neurons from cellular death [18]. Eight weeks post treatment, a signi cant decrease of amyloid plaques was measured, with a shift from a pro-in ammatory to an anti-in ammatory cytokine production, mainly characterized in vitro [17]. Given the discrepant results reported, the mechanisms involved in amyloid load reduction and the effects of LD-RT on the neuroin ammation in the AD brain need further investigation.…”

“…LD-RT has also shown remarkable anti-in ammatory effects in benign and chronic degenerative in ammatory diseases [see ref 14 for a detailed review]. Only four studies have evaluated the LD-RT effect in the context of AD using AD mouse models [15][16][17][18]. In a rst report, authors observed a decrease of amyloid plaques, and accompanied by an improvement of memory performances in a pure amyloid model, more important with a fractionated protocol of LD-RT (5 fractions of 2 Grays (Gy), delivered daily) [15].…”

Low-dose ionizing radiation as a hormetin: experimental observations and therapeutic perspective for age-related disorders

“…In addition, four clinical trials are starting on low-dose radiotherapy of Alzheimer’s disease using 5 or 10 dose fractions of 2 Gy. Such exposures have been employed successfully to remove amyloid plaque in other areas of the body and produce anti-inflammatory effects in preclinical studies (Michael et al 2019 ; Ceyzeriat et al 2020 ; Kim et al 2020a , 2020b ). LDIR was also considered among the potential hormesis-based approaches in treating Parkinson’s disease (Calabrese et al 2018a ).…”