Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer's disease

Abstract

Many neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington's disease, are characterized by the progressive accumulation of abnormal proteinaceous assemblies in specific cell types and regions of the brain, leading to cellular dysfunction and brain damage. Although animal- and in vitro-based studies of NDs have provided the field with an extensive understanding of some of the mechanisms underlying these diseases, findings from these studies have not yielded substantial progress in identifying treatment options for patient populations. This necessitates the development of complementary model systems that are better suited to recapitulate human-specific features of ND pathogenesis. Three-dimensional (3D) culture systems, such as cerebral organoids generated from human induced pluripotent stem cells, hold significant potential to model NDs in a complex, tissue-like environment. In this review, we discuss the advantages of 3D culture systems and 3D modeling of NDs, especially AD and FTD. We also provide an overview of the challenges and limitations of the current 3D culture systems. Finally, we propose a few potential future directions in applying state-of-the-art technologies in 3D culture systems to understand the mechanisms of NDs and to accelerate drug discovery. Graphical abstract.

Keywords: 3D culture; Alzheimer’s disease; Neurodegenerative diseases; cerebral organoids; hiPSCs; tau pathology.

Graphical abstract

Fig. 1

Three-dimensional (3D) modeling of neurodegenerative diseases. The overview of limitations, current progress and future direction in using human induced pluripotent stem cells (hiPSCs)-derived 3D cultures/cerebral organoids (COs) to model Alzheimer’s disease and other neurodegenerative diseases (created with BioRender.com).

Fig. 2

Three-dimensional (3D) modeling of Alzheimer’s disease. Schematic representation of recent studies modeling various aspects of AD using A) 3D cultures, and B) Cerebral organoids. * Studies published as preprints on bioRxiv (created with BioRender.com).