Engineering in Vitro Human Induced Pluripotent Stem Cell-Derived Brain Cell Models for Alzheimer’s Disease and Down Syndrome

Abstract

In disease biology, animal models are widely used. By offering insights on disease etiology, they allow us to systematically examine the complexity of a disease and its mechanisms. However, over the last decade, failures to develop therapeutic interventions resulted in substantial financial burdens on society and demonstrate that translating animal results to humans is not trivial. Although the recent stem cell technologies grant access to human substrates, it has been challenging to capture the ramifications of complicated neurological diseases within an in vitro two-dimensional system. Therefore, there is enormous pressure for better models for human neurological disorders, in particular, neurodegenerative and neurodevelopmental diseases. In this work, I present two case studies demonstrating the use of human induced pluripotent stem cells (iPSCs) combined with genome editing engineering and three-dimensional culture systems to recapitulate pathological phenotypes of the diseases of interest. The first study investigates impacts of a rare variant in Alzheimer's disease (AD)-associated risk gene, ATP-binding cassette transporter subtype A7 (ABCA7), on AD pathologies using isogenic iPSCs. Compared to the control lines derived from a healthy donor, mutant brain cells reveal a number of pathological phenotypes consistent with clinical data. Moreover, I suggest the potential contribution of malfunctioning ABCA7 to AD pathologies by showing links between the aberrant endosomal trafficking phenotypes and AD. In the second study, I utilize three-dimensional culture systems to model Down syndrome (DS) using isogenic iPSCs derived from a DS patient. Limited accessibility to human brains and lack of appropriate in vitro model systems recapitulating the complexity of brain architecture pose a significant challenge in DS studies, particularly in developmental studies of DS. Using the cerebral organoids culture system, I observe that DS cerebral organoids can recapitulate pathological phenotypes of DS and evaluate developmental profiles compared to isogenic disomy iPSCs-derived cerebral organoids. Furthermore, I administer two classes of compounds, one for Alzheimer's disease and another for Down syndrome on DS cerebral organoids to assess the pharmacological effects on recapitulated phenotypes. Together, these studies show that human iPSCs with genome editing and three-dimensional culture systems can serve for mechanistic and therapeutic studies on human brain diseases.