Low-dose proton radiation effects in a transgenic mouse model of Alzheimer’s disease – Implications for space travel

Space radiation represents a significant health risk for astronauts. Ground-based animal studies indicate that space radiation affects neuronal functions such as excitability, synaptic transmission, and plasticity, and it may accelerate the onset of Alzheimer’s disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3 month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0.1–1.0 Gy; whole body) and evaluated functional and biochemical hallmarks of AD. We performed behavioral tests in the water maze (WM) before irradiation and in the WM and Barnes maze at 3 and 6 months post-irradiation to evaluate spatial learning and memory. We also performed electrophysiological recordings in vitro in hippocampal slices prepared 6 and 9 months post-irradiation to evaluate excitatory synaptic transmission and plasticity. Next, we evaluated amyloid β (Aβ) deposition in the contralateral hippocampus and adjacent cortex using immunohistochemistry. In cortical homogenates, we analyzed the levels of the presynaptic marker synaptophysin by Western blotting and measured pro-inflammatory cytokine levels (TNFα, IL-1β, IL-6, CXCL10 and CCL2) by bead-based multiplex assay. TG mice performed significantly worse than WT mice in the WM. Irradiation of TG mice did not affect their behavioral performance, but reduced the amplitudes of population spikes and inhibited paired-pulse facilitation in CA1 neurons. These electrophysiological alterations in the TG mice were qualitatively different from those observed in WT mice, in which irradiation increased excitability and synaptic efficacy. Irradiation increased Aβ deposition in the cortex of TG mice without affecting cytokine levels and increased synaptophysin expression in WT mice (but not in the TG mice). Although irradiation with protons increased Aβ deposition, the complex functional and biochemical results indicate that irradiation effects are not synergistic to AD pathology.

空间辐射对宇航员构成显著健康风险。现有地面动物实验研究证实，空间辐射会影响神经元兴奋性、突触传递与可塑性等功能，还可加速阿尔茨海默病（AD）的发病进程。尽管质子是空间辐射谱的主要组成成分，但目前尚无研究探讨质子辐照对AD相关病理的影响。本研究以3月龄APP/PSEN1转基因（transgenic, TG）小鼠与野生型（wild type, WT）小鼠为实验对象，采用150 MeV质子进行全身辐照（剂量范围0.1–1.0 Gy），并评估AD的功能与生化标志性特征。分别于辐照前、辐照后3个月及6个月，通过水迷宫（water maze, WM）与巴恩斯迷宫开展行为学检测，以评估小鼠的空间学习与记忆能力。此外，于辐照后6个月及9个月制备海马脑片，进行离体电生理记录，以评估兴奋性突触传递与可塑性。随后，采用免疫组织化学法检测小鼠对侧海马与邻近皮层的β淀粉样蛋白（amyloid β, Aβ）沉积情况。在皮层组织匀浆中，通过蛋白质印迹法（Western blotting）分析突触前标志物突触素（synaptophysin）的表达水平，并采用基于磁珠的多重检测法测定促炎细胞因子（TNFα、IL-1β、IL-6、CXCL10与CCL2）的含量。水迷宫实验结果表明，TG小鼠的行为表现显著劣于WT小鼠。对TG小鼠进行质子辐照并未影响其行为学表现，但会降低CA1神经元的群体峰电位振幅，并抑制配对脉冲易化效应。TG小鼠的此类电生理改变与WT小鼠存在本质区别：WT小鼠经质子辐照后，神经元兴奋性与突触效能均显著提升。尽管质子辐照可增加TG小鼠皮层的Aβ沉积，但综合功能与生化层面的实验结果显示，质子辐照并未与AD病理产生协同效应。