Abstract
In humans, apoE, which plays a role in repair, is expressed in three isoforms: E2, E3, and E4. E4 is a risk factor for age-related cognitive decline (ACD) and Alzheimer's disease (AD), particularly in women. In contrast, E2 is a protective factor for ACD and AD. E2 and E4 might also differ in their response to cranial 137Cs irradiation, a form of radiation typically used in a clinical setting for the treatment of cancer. This might be mediated by reactive oxygen species (ROS) in an-apoE isoform-dependent fashion. E2 and E4 female mice received sham-irradiation or cranial irradiation at 8 weeks of age and a standard mouse chow or a diet supplemented with the antioxidant alpha-lipoic acid (ALA) starting at 6 weeks of age. Behavioral and cognitive performance of the mice were assessed 12 weeks later. Subsequently, the generation of ROS in hippocampal slices was analyzed. Compared to sham-irradiated E4 mice, irradiated E4 mice showed enhanced spatial memory in the water maze. This was associated with increased hippocampal PMA-induction of ROS. Similar effects were not seen in E2 mice. Irradiation increased endogenous hippocampal ROS levels in E2 mice while decreasing those in E4 mice. NADPH activity and MnSOD levels were higher in sham-irradiated E2 than E4 mice. Irradiation increased NADPH activity and MnSOD levels in hemi brains of E4 mice but not in those of E2 mice. ALA did not affect behavioral and cognitive performance or hippocampal formation of ROS in either genotype. Thus, apoE isoforms modulate the radiation response.
Highlights
Cancer patients are exposed to 137Cs radiotherapy [1, 2]
This study shows that within the experimental conditions used the effects of 137Cs irradiation on spatial memory retention in the water maze are Apolipoprotein E (apoE) isoformdependent in female mice and are associated with measures of reactive oxygen species (ROS)
Irradiated E4 mice showed greater spatial memory retention than sham-irradiated E4 mice and irradiated E2 mice and this was associated with an www.impactjournals.com/oncotarget increased hippocampal response to Phorbol 12-myristate 13-acetate (PMA)-induction of ROS
Summary
Cancer patients are exposed to 137Cs radiotherapy [1, 2]. While whole brain irradiation (WBI) can be a life-saving treatment for brain metastasis, it is associated with detrimental CNS side effects [1, 3]. WBI can lead to progressive and long-term deficits in cognition, including deficits in attention, speed of information processing, executive function, and learning and memory [4]. The temporal lobe, which includes the hippocampus, is sensitive to cognitive changes following irradiation. Following 137Cs irradiation in rodent models, impairments in performance on hippocampus-dependent cognitive tests, such as contextual fear conditioning and spatial learning and memory in tests requiring navigation, such as the water maze and Barnes maze, have been reported [5]. Other studies have reported enhanced cognitive performance following irradiation [6, 7]. Hippocampusdependent tests differ in sensitivity to detect cognitive impairments following a given radiation exposure [8] and irradiation might differentially affect distinct types of hippocampal-dependent memories
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