Low−dose ionizing radiation alleviates Aβ42−induced cell death via regulating AKT and p38 pathways inDrosophilaAlzheimer′s disease models

Abstract

Ionizing 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.

miR‑132 improves the cognitive function of rats with Alzheimer's disease by inhibiting the MAPK1 signal pathway

“…In the present study, rats were treated with miR-132 analogs and siMAPK1, and the results demonstrated that after p38 signaling pathway was disturbed, the learning ability, memory and brain tissue disorder of AD rats were significantly improved, the apoptosis of nerve cells was decreased, and the serum levels of AChE was significantly decreased. Previous studies on neural and non-neuronal cells have demonstrated that p38 regulates apoptosis through a variety of mechanisms, including activation of p53, as well as phosphorylation of c-JUN and c-fos, induction of Bax transposition, and involvement in Fas-FasL-mediated apoptosis, enhancement of c-myc expression and activation of caspase-3 (35,36). In addition, p38 MAPK can enhance the expression of TNF-α, thereby activating p38-induced apoptosis (37).…”

Pharmacological Treatment of Alzheimer’s Disease: Insights from Drosophila melanogaster

“…After drug administration, nitazoxanide stimulated autophagy and promoted Aβ clearance by inhibiting AKT signaling in-vivo and in-vitro [59]. In contrast, decreased Aβ levels and Aβ deposition in brain were seen in salidroside fed Aβ-Drosophila, which protected neuron-cells from Aβ toxicity by upregulating AKT signaling [60]. Low dose Ionizing radiation suppressed the developmental defects and locomotive dysfunction, but had no effect on survival rates and longevity of Aβ42-expressing flies [61].…”

“…However, some reports suggested that knocking out of mTOR signaling impaired the synaptic plasticity, which can be reversed by up-regulation of mTOR and the loss of mTOR activity may also cause atrophy of AD neurons [85]. Salidroside treatment initiated mTOR activation in AD flies [60]. Considering the role of mTOR in memory formation and function in promoting cognition, it comes as no surprise that excessive activation as well as inactivation of mTOR might be the pathological mechanism behind the cognitive loss and AD progression.…”

Calsyntenin 1 mRNA expression sensitivity to ionizing radiation in human hepatocytes and carcinoma cells and blood cells of BALB/c mice

“…This gene mediates the axonal anterograde transport of specific vesicles that traffic amyloid precursor protein (APP) in Alzheimer disease (AD) (Konecna, Frischknecht, Kinter, Ludwig, Steuble, Meskenaite, Indermühle, Engel, Cen, Mateos, Streit, Sonderegger et al, 2006;Ludwig et al, 2009). The biological effects of LDIR on AD have been investigated (Hwang et al, 2019;Rudobeck et al, 2017). Low-dose ionizing radiation has beneficial effects on the pathogenesis of Aβ42-associated AD (Hwang et al, 2019).…”

“…The biological effects of LDIR on AD have been investigated (Hwang et al, 2019;Rudobeck et al, 2017). Low-dose ionizing radiation has beneficial effects on the pathogenesis of Aβ42-associated AD (Hwang et al, 2019). Irradiation with low-dose protons increases Aβ deposition, but it had no effect on AD pathology (Rudobeck et al, 2017).…”