Exploiting accelerated aging associated with Low Earth Orbit (LEO) environment to gain insights into pathogenesis and treatment of progressive neurological disorders - PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with decline in memory and cognitive skills, eventually leading to the loss of ability to perform simple tasks. While genetics and a family history of AD are major risk factors, age remains the most critical risk factor for late onset AD (LOAD) as the percentage of individuals with AD increases dramatically with age. Accelerated aging in space provides unique opportunities to exacerbate aging related declines in tissue/organ function and amplify pathogenic signaling pathways associated with disease onset and progression. In this project, we are interested in how aging contributes to development and progression of AD. We are also interested in how onset of AD perpetuates dysfunction of other organs and systems, specifically, the heart and the cardiovascular system. To accomplish this, we will use cerebral organoids derived from AD human induced pluripotent stem cells (hiPSCs) cultured in Low Earth Orbit (LEO) (microgravity and ionizing radiation) to promote accelerated aging to study the effect of aging on cellular processes critical in progression of AD. To model how progressive neurodegenerative diseases affect other organs and systems, and vice versa, we will focus on the brain-heart axis. Thus, we will also utilize cardiac organoids generated from hiPSCs (control and AD patients) to study bi- directional communication in the setting of neurodegenerative disease. Finally, as a therapeutic strategy, we will evaluate if elimination of senescent cells with senolytic treatment in aged cerebral organoids can slow progression of hallmarks of AD including accumulation of beta-amyloid peptide (Aβ) and Tau tangles. Using an organoid model of accelerated aging, we hypothesize: (a) Aging exacerbates pathogenic APP processing and pTau resulting in enhanced Aβ deposition and Tau tangles, as well as DNA damage/loss of repair, (b) bi- directional communication between the heart and the brain in the setting of progressive neurodegenerative disease results in cardiac dysfunction, and (c) elimination of senescent cells will slow or mitigate progressive neurodegeneration associated with aging. Completion of the UG3 phase will result in: (a) successful terrestrial development of an AD cerebral organoid system and associated pathology, (b) confirmation that accelerated aging associated with LEO increases pathogenic APP processing, hyper-phosphorylation of Tau (pTau) and DNA damage, resulting in accumulation of Aβ and Tau tangles, and (c) demonstration that culture medium from AD cerebral organoids can perpetuate cardiac dysfunction. Results from the UG3 phase will inform studies proposed in the UH3 phase and technical milestones for the UH3 phase will include (a) establishing co-culture of AD cerebral and cardiac organoids in space and (b) determining if elimination of senescent cells via senolysis can be used as an effective therapeutic strategy to mitigate or slow progressive neurodegeneration associated with aging and prevent cardiac dysfunction.
