Abstract
ABSTRACTIonizing radiation is widely used in medicine and is valuable in both the diagnosis and treatment of many diseases. However, its health effects are ambiguous. Here, we report that low-dose ionizing radiation has beneficial effects in human amyloid-β42 (Aβ42)-expressing Drosophila Alzheimer's disease (AD) models. Ionizing radiation at a dose of 0.05 Gy suppressed AD-like phenotypes, including developmental defects and locomotive dysfunction, but did not alter the decreased survival rates and longevity of Aβ42-expressing flies. The same dose of γ-irradiation reduced Aβ42-induced cell death in Drosophila AD models through downregulation of head involution defective (hid), which encodes a protein that activates caspases. However, 4 Gy of γ-irradiation increased Aβ42-induced cell death without modulating pro-apoptotic genes grim, reaper and hid. The AKT signaling pathway, which was suppressed in Drosophila AD models, was activated by either 0.05 or 4 Gy γ-irradiation. Interestingly, p38 mitogen-activated protein-kinase (MAPK) activity was inhibited by exposure to 0.05 Gy γ-irradiation but enhanced by exposure to 4 Gy in Aβ42-expressing flies. In addition, overexpression of phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, or a null mutant of AKT strongly suppressed the beneficial effects of low-dose ionizing radiation in Aβ42-expressing flies. These results indicate that low-dose ionizing radiation suppresses Aβ42-induced cell death through regulation of the AKT and p38 MAPK signaling pathways, suggesting that low-dose ionizing radiation has hormetic effects on the pathogenesis of Aβ42-associated AD.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by the presence of amyloid plaques, intracellular neurofibrillary tangles, progressive neuronal loss and gradual memory deterioration (Dickson, 2001; Selkoe, 2001)
Aβ42-mediated cell death in the brains of both AD patients and animal AD models has been linked to various molecular signals including activation of mitogenactivated protein kinases (MAPKs) such as p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), as well as suppression of phosphoinositide 3-kinase (PI3K)/AKT and glycogen synthase kinase-3 (GSK-3) (Zhu et al, 2001; Pearson et al, 2006; Ma et al, 2007; Young et al, 2009; Sofola et al, 2010; Tare et al, 2011; Yin et al, 2011; Povellato et al, 2013)
4 Gy of γ-irradiation enhanced the wing shrinkage of the Aβ42expressing flies (Fig. 1C,D). These results suggest that low-dose ionizing radiation has beneficial effects on the developmentally defective phenotypes in Drosophila AD models
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by the presence of amyloid plaques, intracellular neurofibrillary tangles, progressive neuronal loss and gradual memory deterioration (Dickson, 2001; Selkoe, 2001). Aβ42-mediated cell death in the brains of both AD patients and animal AD models has been linked to various molecular signals including activation of mitogenactivated protein kinases (MAPKs) such as p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), as well as suppression of phosphoinositide 3-kinase (PI3K)/AKT and glycogen synthase kinase-3 (GSK-3) (Zhu et al, 2001; Pearson et al, 2006; Ma et al, 2007; Young et al, 2009; Sofola et al, 2010; Tare et al, 2011; Yin et al, 2011; Povellato et al, 2013). These pathways are being explored as potential drug targets in the treatment of AD, such as inhibition of the AKT/GSK-3β signaling pathway, for example (Van Dam and De Deyn, 2017)
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