Using hPSC-derived organoids to characterize age-associated changes in cortical cell metabolism and their role in neurodegeneration

Aging is the primary risk factor for neurodegeneration impacting changes at the cell and molecular level. Primary hallmarks of aging are centered around dysregulated metabolism and perturbed bioenergetics, both which are heavily implicated in Alzheimer‚Äôs disease (AD). However, the mechanisms in which dysregulated metabolism contributes to the onset of AD hallmarks remains unknown thus preventing the development of effective treatments. There is a need to understand how changes in metabolic function impact cortical health in order to identify the molecular drivers of disease onset. This work leverages 3D cortical organoids (hCOs), derived from human pluripotent stem cells, to characterize changes in metabolic state across cortical aging and assess their contribution to neurodegenerative phenotypes. We demonstrate that long-term hCOs recapitulate mature cortical cell composition and observe sporadic onset and progression of AD hallmarks across one year in culture. Using a combination of single cell RNA sequencing and molecular biology assays, we identify discrete alterations in core energy metabolism and homeostatic functions in neurons and astrocytes from AD patient tissue, with correspondence to degenerating hCOs. Molecular features of human pathology conserved in vitro will be targeted in follow-up studies using functional perturbations and metabolomics-based analyses to uncover their role in the development of sporadic disease. Collectively, this work conveys the relationship between metabolic dysregulation and AD pathogenesis and provides a framework to determine the mechanisms involved in these processes with in vitro models.