Spaceflight modulates neurodegeneration-associated transcriptomic pathways across brain cell types

Spaceflight induces stress that damages tissues and promotes disease. The brain may be particularly vulnerable due to its high bioenergetic demand and to microgravity-induced headward fluid shifts that impose mechanical and vascular stress. Prior work has shown that spaceflight can alter the structure and function of the brain and reshape its transcriptome in ways that implicate disease-relevant gene pathways. Here, we used single-nucleus transcriptomic analyses to test whether spaceflight engages neurodegeneration-associated transcriptional programs and activates disease-associated microglia. Young (3 months) or older (7 months) female mice were flown to the International Space Station or retained as terrestrial controls for 55–58 days before euthanasia. Brain nuclei were processed for single-nucleus RNA sequencing, annotated, and grouped into seven primary cell types. All cell types exhibited large numbers of differentially expressed genes as a function of spaceflight, whereas few genes were affected by age. Pathway analysis showed that these genes were enriched for processes upstream of neurodegenerative pathology, including mitochondrial and oxidative stress, proteostasis, and cell death, rather than for brain-specific outcomes such as synaptic and neuroplasticity pathways. Spaceflight further drove an increase in microglial gene signatures associated with activated states, including disease-associated, MHC-II, interferon-responsive, and inflammatory microglia. Together, these findings indicate that spaceflight induces a transcriptional landscape consistent with elevated risk for neurodegenerative disease, likely reflecting cellular sensitization rather than established pathology at this exposure duration. These results underscore the need for further studies to define relative risk and to identify countermeasures as human missions venture farther and longer into space.