Enhanced Neuronal Activity and Asynchronous Calcium Transients Revealed in a 3D Organoid Model of Alzheimers Disease

Abstract

Advances in the development of three-dimensional (3D) brain organoids maintained in vitro have provided excellent opportunities to study brain development and neurodegenerative disorders, including Alzheimers disease (AD). However, there remains a need to generate AD organoids bearing patient-specific genomic backgrounds that can functionally recapitulate key features observed in the AD patients brain. To address this need, we successfully generated cerebral organoids from human pluripotent stem cells (hPSCs) derived from a familial AD patient with a mutation in presenilin 2 (PSEN2). An isogenic control hPSC line was generated using CRISPR-Cas9 technology. Both organoids were characterized by analysing their morphology, A{beta}42/A{beta}40 ratio and functional neuronal network activity. It was found that AD organoids had a higher A{beta}42/A{beta}40 ratio, asynchronous calcium transients and enhanced neuronal hyperactivity, successfully recapitulating some aspects of AD pathology. Therefore, our study presents a promising organoid-based biosystem for the study of the pathophysiology of AD and a platform for drug development for neurodegenerative disorders.