Alzheimer's in 3D culture: challenges and perspectives

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, and there is currently no cure. The "β-amyloid cascade hypothesis" of AD is the basis of current understanding of AD pathogenesis and drug discovery. However, no AD models have fully validated this hypothesis. We recently developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three-dimensional (3D) cell culture system. These cells were able to recapitulate key events of AD pathology including β-amyloid plaques and neurofibrillary tangles. In this review, we will discuss the progress and current limitations of AD mouse models and human stem cell models as well as explore the breakthroughs of 3D cell culture systems. We will also share our perspective on the potential of dish models of neurodegenerative diseases for studying pathogenic cascades and therapeutic drug discovery.

Keywords: 3D culture; APP; Alzheimer's disease; human stem cell; presenelin.

Fig. 1. Impact of 2D vs 3D cell culture systems on β-amyloid aggregation

Matrigel-based 3D culture conditions promote aggregation of secreted Aβ species from FAD ReN cells.

Fig. 2. Timeframe of AD pathologies in 3D FAD ReN cells

Extracellular Aβ aggregates develop ~6 weeks after differentiation and tauopathy is evident from ~10–14 weeks after differentiation. Day 0 indicates the day on which cells are seeded with Matrigel.