Human iPSC-Derived Neural Models for Studying Alzheimer's Disease: from Neural Stem Cells to Cerebral Organoids

Abstract

During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study mechanisms of human neural development, disease modeling, and drug discovery in vitro. Especially in the field of Alzheimer's disease (AD), where this treatment is lacking, tremendous effort has been put into the investigation of molecular mechanisms behind this disease using induced pluripotent stem cell-based models. Numerous of these studies have found either novel regulatory mechanisms that could be exploited to develop relevant drugs for AD treatment or have already tested small molecules on in vitro cultures, directly demonstrating their effect on amelioration of AD-associated pathology. This review thus summarizes currently used differentiation strategies of induced pluripotent stem cells towards neuronal and glial cell types and cerebral organoids and their utilization in modeling AD and potential drug discovery.

Keywords: Alzheimer’s disease; Astrocytes; Cerebral organoids; In vitro differentiation; Microglia; Neural differentiation; Neural progenitors; Neural stem cells; Neurons; iPSCs.

Fig. 1

Differentiation protocols. Summary of neurodifferentiation strategies to generate specific cell types of the central nervous system from stem cells. For each strategy, we list major growth factors, small molecules, and other reagents that must be added to the cell culture media. Media also often contain N2 and B27 Supplements. Thus, for complete protocols, refer to the respective references listed in the last column

Fig. 2

Major finding from stem-cell-based models of AD. For each cell type, we summarize significant results presented in Sect. 3. “↑” represents upregulation or increase, “↓” represents downregulation or decrease