Exposure to⁵⁶Fe-Particle Radiation Accelerates Electrophysiological Alterations in the Hippocampus of APP23 Transgenic Mice

Abstract

An unavoidable complication of space travel is exposure to high-charge, high-energy (HZE) particles. In animal studies, exposure of the CNS to HZE-particle radiation leads to neurological alterations similar to those seen in aging or Alzheimer's disease. In this study we examined whether HZE-particle radiation accelerated the age-related neuronal dysfunction that was previously described in transgenic mice overexpressing human amyloid precursor protein (APP). These APP23 transgenic mice exhibit age-related behavioral abnormalities and deficits in synaptic transmission. We exposed 7-week-old APP23 transgenic males to brain-only (56)Fe-particle radiation (600 MeV/nucleon; 1, 2, 4 Gy) and recorded synaptic transmission in hippocampal slices at 2, 6, 9, 14 and 18-24 months. We stimulated Schaeffer collaterals and recorded field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) in CA1 neurons. Radiation accelerated the onset of age-related fEPSP decrements recorded at the PS threshold from 14 months of age to 9 months and reduced synaptic efficacy. At 9 months, radiation also reduced PS amplitudes. At 6 months, we observed a temporary deficit in paired-pulse inhibition of the PS at 2 Gy. Radiation did not significantly affect survival of APP23 transgenic mice. We conclude that irradiation of the brain with HZE particles accelerates Alzheimer's disease-related neurological deficits.

Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer’s Disease

“…One example is a defect in neurogenesis, which has been documented in response to traditional radiotherapy [38] as well as exposure to 56 Fe particles [5], [7], [39]. In addition to neuronal proliferation defects, impaired cognition could also result from inhibition of long-term potentiation (LTP) [40], an effect which has been reported with 56 Fe particle irradiation in the APP23 transgenic mouse model of AD [41].…”

A Single Low Dose of Proton Radiation Induces Long-Term Behavioral and Electrophysiological Changes in Mice

“…Therefore, we (14) and others (13) hypothesized that exposure to radiation may accelerate the onset of neurodegenerative diseases, such as Alzheimer's disease. The common hallmarks of Alzheimer's disease and radiation exposure include oxidative stress markers (15)(16)(17), which have been associated with impaired synaptic plasticity (18,19).…”

“…Inhibition of neurogenesis could be detected after whole-body irradiation with proton doses as low as 0.5 Gy (28). Although several functional decrements in Alzheimer's disease (29)(30)(31)(32) and in the irradiated brain (14,33) are clearly similar and are likely related, the effects of radiation on other, perhaps less obvious but significant, functional manifestations in Alzheimer's disease have never been tested. For example, the propensity for epileptiform activity (34) and altered oscillatory properties in the local hippocampal networks (35,36) have been described in Alzheimer's disease, but have never been tested in irradiated neuronal tissue.…”

“…Two different mouse transgenic strains, APP23 (14) and APP/PSEN1DE9 mice (20), have been used to study the effect of charged particle radiation on Alzheimer's diseaserelated pathology, behavior and electrophysiology functions. Here, we report our findings on the long-term behavioral and electrophysiological effects of 0.5 Gy proton-radiation dose in a strain of B6C3F1/J wild-type mice that are used by Jackson Laboratory as a background strain to generate the commonly used and commercially available APP/PSEN1DE9 transgenic mice [strain name, B6C3-Tg(APPswe,PSEN1DE9)85Dbo/Mmjax].…”

Does ionizing radiation influence Alzheimer's disease risk?

“…A certain amount of interest has been given to the potential risks (including AD risks) associated with space travel. A recent report has shown that exposure to high energy 56 Fe 26+ iron nuclei accelerated age-related neurological dysfunction in APP23 transgenic mice overexpressing human APP [99]. Knowing that AD was often described as a process similar to accelerated ageing [100], the authors concluded that exposure to cosmic high-energy particles might accelerate AD-related neurological deficits.…”