Long-term CNS Effects of Low Dose GCRsim and Gamma Irradiation in Male and Female Wildtype and Alzheimer's-like Mice

Khyrul Khan, BA
Department of Neurology
Division of Aging
Poster Overview

Today, manned deep space missions are becoming an increasingly achievable reality. This emphasizes the need to study the effects of space radiation on humans, especially with regards to sex differences. To better comprehend radiation effects on cognition and cardiac health, we irradiated two cohorts of 4 month-old male and female wildtype (WT) and Alzheimer’s disease- like (APP/PS1dE9) mice with either sham, 0.5 Gy, or 0.75 Gy simulated space-like radiation (GCRsim) or 0.75 Gy or 2 Gy gamma irradiation. A subset of mice underwent behavioral testing 8 months later, and another subset underwent brain and heart MRI scans before and after irradiation. While combined analyses for the two cohorts are underway, to date we have seen that WT males that received 0.75 Gy GCRsim and 2 Gy gamma irradiation showed impaired spatial memory. MRI scans revealed some structural differences in the brain from pre-irradiation to post-irradiation but no radiation-specific dose effects in the heart. Female APP/PS1dE9 mice from the first cohort had higher levels of an insoluble form of amyloid-beta protein, which accumulates as plaques in the Alzheimer’s brain. Biochemical analysis from the second cohort is underway. Taken together, our study suggests deep-space radiation may have subtle but long-lasting effects on brain.

Scientific Abstract

Prolonged exposure to highly charged particles in deep space may predispose astronauts to increased CNS or cardiovascular deficiencies. In our current study, wildtype (WT) and Alzheimer’s-like APP/PS1dE9 (Tg) mice were divided into two cohorts and received a whole- body dose of 0, 0.5 or 0.75 Gy 5-ion mixed beam (GCRsim), or 0.75 or 2 Gy gamma at 4 months. For each cohort, a subset of mice underwent behavioral testing at 11-12 months and another subset underwent pre- and post-IRR brain and heart MRI scanning at 3.5 and 11.5 months. Behavioral data from both cohorts suggests cognitive impairment in the Spatial Novelty Y-Maze in male WT 0.75 Gy GCRsim and 2 Gy gamma irradiated mice. Pre- vs. Post-IRR brain MRI analysis shows increased ventricular and hippocampal volume, and reduced cortical volume in both WT and Tg mice, although no significant sex and dose interaction was observed. No radiation-specific effects were observed in cardiac MRI regarding ejection fraction, stroke volume index or left ventricular wall thickness. Amyloid-beta ELISA analysis from the 1st cohort confirmed higher insoluble Abeta 1-42 levels in female Tg mice but revealed no significant radiation effects. Further biochemical and behavioral analyses are pending.

Clinical Implications
This research is relevant to the cognitive health of astronauts and cancer patients undergoing gamma radiation, particularly those at risk for Alzheimer’s disease. Our findings suggest that cognitive impairment, particularly in males, may result from these treatments, meriting further investigation.
Research Areas
Authors
Khyrul Khan, Maren Schroeder, Brittani Price, Barbara Caldarone and Cynthia Lemere
Principal Investigator
Dr. Cynthia Lemere

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