Combined Ionizing Radiation Caused Cognition and Non-Cognition Behavior Benefits and Modulated Microglial Activity in Wild-Type and Alzheimer’s-like Transgenic Mice

TL;DR

This study shows that combined ionizing radiation can improve cognitive and non-cognitive behaviors in mice and modulate brain inflammation, suggesting a potential new treatment for Alzheimer’s disease.

Contribution

The study demonstrates that combined ionizing radiation modulates microglial activity and provides behavioral benefits in Alzheimer’s models.

Findings

Combined ionizing radiation improved cognitive and non-cognitive behaviors in all tested mouse lines.

Irradiation increased cytokine levels in the prefrontal cortex of C57Bl/6 and Tau P301S mice.

5xFAD mice showed a limited re-balancing effect of cytokine content after irradiation.

Abstract

There is currently no effective treatment for Alzheimer’s disease (AD). Neuroinflammation is considered one of the promising targets for the treatment of AD and other proteinopathies. Moreover, several studies have suggested that ionizing radiation (IR) could be an effective method for targeting neuroinflammation. In this study, we examined the effects of combined IR (gamma rays and high-energy carbon-12 nuclei) on AD-related behavioral symptoms and cytokine content in the prefrontal cortex and hippocampus of 5xFAD and Tau P301S mice lines (transgenic models of AD), as well as naïve C57Bl/6 mice. The results showed that IR exposure resulted in cognitive and non-cognitive behavioral benefits in all mouse lines used. Alongside this, the C57Bl/6 and Tau P301S irradiated mice showed an increase in cytokine content predominantly in the prefrontal cortex. In contrast, the 5xFAD mice showed a limited “re-balancing” effect of IR exposure on cytokine content. Thus, the results indicate the potential use of combined radiotherapy in the treatment of AD.

Alzheimer’s disease (AD) is one of the primary causes of disability and dependency among aging populations worldwide. Neuroinflammation may be a potential therapeutic target in AD. Moreover, ionizing radiation may be a tool for modulating neuroinflammation. Here, we used three mouse lines—C57Bl/6 and the transgenic AD models 5xFAD and Tau P301S—to investigate the effects of combined ionizing radiation (γ-rays and carbon-12 nuclei) on emotional state, cognitive abilities, and markers of microglial activation. The obtained data show that combined irradiation results in enhanced exploratory behavior and spatial learning in the C57Bl/6 mice. The same changes, as well as a decrease in anxiety, were found in the Tau P301S mice. Irradiation of the 5xFAD mice resulted in improved welfare and ability to discriminate odors. At the same time, irradiation led to an increase in the level of pro- and anti-inflammatory cytokines in the prefrontal cortex and, to a lesser extent, in the hippocampus of the C57Bl/6 and Tau P301S mice. An increase in macrophage inflammatory protein-1α in the prefrontal cortex and a decrease in interleukin 2β in the hippocampus were found in the 5xFAD mice. Taken together, our data indicate that ionizing radiation exposure is an adequate tool to modulate microglial activity in the brain and may provide cognitive and non-cognitive behavioral benefits in neurodegenerative disease conditions.

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