Ella Zeldich

Intellectual deficits and early-onset Alzheimer’s disease (AD) are hallmarks of Down syndrome. Individuals with Down syndrome represent the largest group of AD patients under the age of 65. Her research focuses on understanding neuronal and glial cell dysfunction, as well as the predisposition to AD-related pathology caused by the triplication of genes on chromosome 21. She employs three-dimensional, induced pluripotent stem cell (iPSC)–derived cortical organoids that mimic early human brain development and recapitulate key neurodegenerative phenotypes associated with trisomy 21. Using these models, she investigates altered differentiation trajectories, neuronal and synaptic connectivity, changes in myelination, and AD-related alterations that characterize Down syndrome brain. Her goal is to identify critical windows of disruption and potential therapeutic targets to improve cognitive outcomes in individuals with Down syndrome.

Specifically, they are exploring the following questions:

– What is the effect of trisomy 21 on oligodendrocyte development and myelin biology? What are the longitudinal changes, and to what extent are these changes driven by epigenetic dysregulation?

– What are the early transcriptomic and functional changes in trisomic neurons that may be associated with the onset of AD pathology? How can we elucidate these changes through the xenotransplantation of cortical organoids into the mouse brain?

– What is the specific role of HMGN1, an epigenetic modulator, in global transcriptomic dysregulation and the altered developmental trajectory of neural lineages?