Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of 56Fe Irradiation on the Brain

Abstract

Purpose In humans, apolipoprotein E (apoE) is encoded by three major alleles (ε2, ε3, and ε4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of 56Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk. Methods and Materials We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after 56Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis. Results In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice. Conclusions The short-term effects of 56Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.

Mitigating effect of EUK-207 on radiation-induced cognitive impairments

“…A dissociation between cognitive performance in the water maze and contextual learning in fear conditioning was previously reported [38, 39]. Consistent with the current study, whole-body high-LET irradiation affected water maze performance, but not contextual fear conditioning within one month following radiation exposure in human apoE mice [40] or 13 months following high LET irradiation [41]. These data emphasized the importance of including different hippocampus-dependent cognitive tests in assessing effects of irradiation on the brain.…”

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…The age at evaluation and irradiation affects the responses to charged particles (Rabin et al 2012) and X-rays (Forbes et al 2014). Sex and genotype (e.g., ApoE allele and ATM) are important variables (Acevedo et al 2008;Benice and Raber 2009;Haley et al 2012;Higuchi et al 2002;Villasana et al 2006Villasana et al , 2011Yamamoto et al 2011;Yeiser et al 2013;Johnson et al 2014;Parihar et al 2014). Additionally, observations comparing head only-, body only-, or whole body-irradiated animals demonstrate a significant role for the periphery in determining behavioral responses .…”

Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex

“…Manda et al showed that 56 Fe (1.5 Gy at 500 MeV/n) increased the time male wild-type mice needed to locate the hidden platform in the water maze 30 days following irradiation but not at earlier time points [19, 20]. Recently, we showed early cognitive effects two weeks following 56 Fe irradiation in wild-type (0.1 Gy at 500 MeV/n)[21] and human apoE mice (0.5 Gy at 500 MeV/n) [22]. …”