Thesis title: Effects of microgravity on behavior and amyloid aggregation in transgenic Caenorhabditis elegans lines expressing human Aβ1-42
With increasing environmental pressures on Earth, long-term space travel may become a necessity, raising questions about the physiological effects of microgravity (µg) and cosmic radiation. Despite advances in space biomedicine, the molecular mechanisms underlying neurodegenerative diseases under these conditions remain poorly understood.
Microgravity has been shown to affect protein homeostasis, including protein folding and aggregation. To investigate the impact of microgravity on β-amyloid (Aβ), the main pathological hallmark of Alzheimer's disease, I used transgenic lines of Caenorhabditis elegans that constitutively express human Aβ1-42 in either neurons or body wall muscles, enabling phenotypic analyses under both normal and simulated microgravity conditions.
Both neuronal and muscular expression of Aβ1-42 impaired locomotion compared to isogenic controls. However, only the line expressing Aβ1-42 in muscles showed reduced pharyngeal pumping associated with lifespan extension, probably due to caloric restriction. In contrast, neuronal expression of Aβ1-42 reduced lifespan without affecting pharyngeal pumping. Immunofluorescence analysis confirmed tissue-specific Aβ1-42 deposition.
Animals were exposed for 48 hours to simulated microgravity environment using the Rotary Cell Culture System (RCCS) developed by NASA. Data were collected from transgenic lines and their isogenic controls, at multiple time points (T4, T8, and T12; T0 corresponds to the young adult (YA) stage, T1 to day 1 of adulthood, and so on). Immunofluorescence analyses at T8 and T12 in animals expressing Aβ1-42 in muscles revealed differences between Earth gravity and microgravity conditions. Locomotion, survival, and pharyngeal pumping assays consistently indicate that microgravity modulates worm behavior, particularly in the presence of Aβ expression.
Overall, these findings contribute to our understanding of gene-environment interactions in neurodegeneration. By combining a genetically defined model with a controlled space analogue system, this study provides a framework to assess whether therapeutic strategies targeting Aβ aggregation, such as monoclonal antibodies retain their efficacy under microgravity conditions. These results may inform the development of neuroprotective approaches for long-duration space missions while also providing translational insights for neurodegenerative diseases on Earth.