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Understanding Down Syndrome-related Neuronal and glial dysfunction using cortical organoids

Ella Zeldich, PhD

Assistant Professor of Anatomy and Neurobiology,

Boston University


Down Syndrome (DS) is caused by triplication of human chromosome 21 (HSA21), resulting in intellectual disability, neuronal dysfunction, aberrant myelination, and early onset Alzheimer’s Disease (AD). Knowledge of how DS affects brain development is incomplete, as research is scant in human tissue to understand how different types of brain cells are affected by the gain of an extra chromosome. While HSA21 gene triplications affect all brain cells, behavioral and cognitive deficits ultimately reflect neuronal network dysfunctions. Mechanistic understanding of altered neuronal activity is limited, as functional studies in DS individuals are not feasible and the currently available animal models for DS have considerable shortcomings. To overcome these limitations and comprehensively assess the impact of trisomy on neuronal activity and connectivity in human cells, we utilized an induced pluripotent stem cell (iPSC)-derived cellular system of cortical organoids (COs).

In my talk, I will cover the utility of the CO model to recapitulate transcriptomic and structural changes as well as the features related to AD pathology in trisomy based on the published and unpublished studies coming from my lab. I will highlight the changes in neuronal activity in trisomic COs recently unraveled by my team and describe how the xenotralsplantations on COs in mouse cortex can advance our understanding of abnormal neuronal activity related to trisomy 21. Finally, I will present the data exposing the therapeutic potential of extracellular vesicles to mitigate DS and DS-AD related pathology. iPSC-derived model of COs presents a comprehensive system for experiments aimed to illuminate pathomechanisms driving neuronal dysfunction and AD pathology in trisomy and provide a unique platform for future pharmacological, genomic, and behavioral studies.   

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