Sex-Specific Neurodegeneration Risks from Space Radiation: Investigating Tau Pathology and Alzheimer's Predisposition in Female Brains

Abstract:

As space missions increasingly include women, it is imperative to understand the neurological risks posed by cosmic radiation. Women already face a higher lifetime risk for Alzheimer’s disease, and the presence of high-energy charged particles in space (such as HZE ions) poses a unique threat to brain health. This study aims to investigate how space radiation impacts tau pathology and neurodegeneration in females, particularly those genetically predisposed to Alzheimer's. By analyzing behavioral outcomes, amyloid/tau burden, and neuroinflammation markers in irradiated female transgenic mice, the project seeks to develop sex-specific insights into the interaction between radiation exposure and neurodegenerative vulnerability. Findings will guide risk mitigation strategies for female astronauts and enhance the design of safer, more inclusive long-term space missions.

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Introduction:

The exploration of space has always been a monumental milestone in human achievement. However, as we venture further into the cosmos, it is crucial to consider the unique challenges posed by space environments, particularly the impact of space radiation on the human body. With NASA and other space agencies increasingly focusing on missions that involve female astronauts, understanding how space radiation affects the female brain becomes not only a scientific imperative but also a matter of equity and safety. Women are inherently more predisposed to neurodegenerative diseases like Alzheimer’s due to genetic and hormonal factors (Bonda et al., 2010). This raises a critical question: How does the radiation in space, particularly the highly charged ions (HZE particles), exacerbate these conditions in women astronauts?

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While much research has been dedicated to the effects of space radiation on male astronauts, there remains a significant gap in understanding how this radiation interacts with the female brain, especially in relation to Alzheimer’s disease pathology. This proposal aims to bridge this gap by examining how space radiation, such as HZE particles and protons, can accelerate neurodegeneration in women and whether this knowledge can help optimize future space missions by mitigating health risks.

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The exploration of this topic is crucial not only for the advancement of space exploration but also for ensuring the well-being of female astronauts, ultimately enabling more inclusive and safer missions into space. By understanding the potential neurotoxic effects, we can take vital steps toward developing preventive strategies that protect the astronauts' health, potentially enhancing their performance and safety during extended space missions.

 

Literature Review:

Previous research has consistently shown that space radiation can aggravate Alzheimer's-like pathology in murine models. Cherry et al. (2012) demonstrated increased amyloid beta deposition following iron particle radiation in transgenic mice. Krukowski et al. (2018) later observed that female mice may exhibit some resilience to behavioral disruptions caused by radiation, suggesting a complex interplay between sex, radiation type, and genetic predisposition.

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Notably, Sergott et al. (2021) investigated proton radiation effects in Alzheimer’s and wild-type mice, identifying long-term behavioral and pathological differences influenced by both sex and genotype. While this study represents a major step forward, it left several key questions open: Why are female mice affected differently? Does radiation impact tau pathology in a sex-specific manner? And what are the long-term neuroinflammatory responses in predisposed female brains?

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By addressing these gaps, the proposed study will not only clarify biological responses in female models but will also help guide tailored neuroprotective interventions. These findings are crucial for ensuring that women can safely and equitably participate in future deep-space missions, with minimized risks for radiation-induced neurodegeneration.

 

Methodology:​ 

This study will use the 3xTg-AD transgenic mouse model, which develops both amyloid beta and tau pathologies. Female mice, aged 9 months, will be divided into control (sham), proton-irradiated (0.5 and 2 Gy), and HZE-irradiated (iron, 100 cGy) groups. Following irradiation at NASA's Space Radiation Laboratory, mice will be monitored for 7 months post-exposure.

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At 16 months of age, all animals will undergo a behavioral battery including contextual fear conditioning (CFC), novel object recognition (NOR), and elevated plus maze (EPM) to assess memory and anxiety-related behaviors. Brain tissues will then be harvested for immunohistochemical analysis of amyloid plaques, phosphorylated tau, microglial activation, and markers of oxidative stress. Additionally, RNA sequencing will be used to examine differential gene expression related to neuroinflammation and neurodegeneration pathways.

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Outcomes will be compared across radiation conditions to evaluate whether tau pathology and neuroinflammatory profiles differ in irradiated versus control females, with attention to dose-dependent effects.

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Conclusion:

The inclusion of women in deep-space missions demands that we move beyond generalized risk models and address sex-specific vulnerabilities. By focusing on how radiation influences tau pathology and neuroinflammatory responses in female Alzheimer’s-prone brains, this study fills a critical research gap. The results will help shape radiation shielding requirements, pharmacological countermeasures, and pre-mission screening protocols tailored to women. More broadly, it supports the ethical imperative of enabling equal participation in space exploration while safeguarding long-term cognitive health.

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References :

Cherry, J. D., Liu, B., Frost, J. L., Lemere, C. A., Williams, J. P., & Olschowka, J. A. (2012). Galactic cosmic radiation leads to cognitive impairment and increased Aβ plaque accumulation in a mouse model of Alzheimer’s disease. PLoS One, 7(12), e53275. https://doi.org/10.1371/journal.pone.0053275

 

Krukowski, K., Grue, K., Frias, E. S., Pietrykowski, J., Jones, T., Nelson, G., & Rosi, S. (2018). Female mice are protected from space radiation-induced maladaptive responses. Brain, Behavior, and Immunity, 74, 106–120. https://doi.org/10.1016/j.bbi.2018.08.003

 

Santos, C. Y., Snyder, P. J., Wu, W. C., Zhang, M., Echeverria, A., & Alber, J. (2020). Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 12(1), e12091. https://doi.org/10.1002/dad2.12091

 

Sergott, T. M., Nelson, G. A., Nencka, A. S., Cheung, J., Asher, A., & Limoli, C. L. (2021). Whole-body proton radiation alters behavior and Alzheimer’s pathology in a sex- and genotype-specific manner. npj Microgravity, 7(1), 37. https://doi.org/10.1038/s41526-021-00143-0