Abstract
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.
Highlights
The space radiation environment is characterized by the presence of charged particles dominated by protons and helium nuclei originating mainly from the solar activity and, in lesser amounts, by fully ionized nuclei of all heavier elements often denoted as high charge (Z), high energy (E) particle radiation (HZE) originating from galactic cosmic rays
We considered it important to confirm that differences in swim distance in spatial tests were not caused by sensory-motor or motivational decrements, which had been reported in this strain of TG mice, at a much older age of 20–26 months of age [77]
At 6 months, ANCOVA confirmed the significance of such genotype-related decrements in the Spatial 2 tests (Fig 2, bottom panels A, B; F1,67 = 15.52, p
Summary
The space radiation environment is characterized by the presence of charged particles dominated by protons and helium nuclei originating mainly from the solar activity and, in lesser amounts, by fully ionized nuclei of all heavier elements often denoted as high charge (Z), high energy (E) particle radiation (HZE) originating from galactic cosmic rays. The charged particles deposit their energy along their tracks in the process defined by linear energy transfer (LET) When they traverse biological tissues, the intense ionization along the linear particle tracks may impart significant damage to cells and subcellular structures [1]. Similar to the normal aging process and AD [23], increased oxidative stress has been reported in neuronal tissue after a single low dose exposure to ionizing radiation [24, 25], which has been associated with behavioral decrements [26]. Whereas the formation of reactive oxygen species peaks along the particle tracks within nano- to milliseconds after traversal through the CNS tissue, a lasting shift in the redox balance can be observed in neuronal cell lines in vitro [27], and in the hippocampus in vivo, indicating the presence of chronic oxidative stress [28]. In AD, elevated brain levels of TNFα, IL-1 and IL-6 have been
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