Alzheimer's in 3D culture: Challenges and perspectives

Abstract

Summary 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.

Recapitulating Amyloid ß and Tau Pathology in Human Neural Cell Culture Models—Clinical Implications

“…Our studies clearly demonstrated the advantage of using human neural cell culture systems in recapitulating Aβ-induced tauopathy, which was not feasible in mouse models 44–46 . Our 3D human cellular AD model can also provide a powerful platform for HTS of candidate AD drugs that can reduce Aβ and/or tau pathology in a single system, which is not possible in current AD models (Fig.…”

“…By generating human neural stem cell lines carrying multiple mutations in APP together with PS1, we achieved high levels of pathogenic Aβ42 comparable to those in brains of AD patients 44–46 . Co-expression of multiple FAD mutations in APP and PS1 has been previously employed for generations of various AD transgenic mouse models.…”

“…1). Also, our 3D culture systems allow scalable plating techniques, from thick-layer 6- and 24-well formats to a 96-well thin-layer design, which can fit large scale HTS or high-content screening (HCS) 44–46 . An additional strength of our immortalized and single-clonal human neural progenitor cells is their rapid proliferation and stability throughout repeated passages.…”

“…As shown by Muratore et al ., the efficacy of Aβ neutralizing antibodies can also be tested in human neural cell culture model of AD 28 . In addition to the impact on toxic Aβ species, our 3D culture model can test if these antibodies can block tau pathologies in 3D human neural cell culture systems 44–46 . Human cellular AD models can also be used to determine optimal doses of candidate AD drugs to block Aβ and/or tau pathology without affecting neuronal survival (Fig.…”

Three‐Dimensional Models of the Human Brain Development and Diseases

“…[12] We were able, for the first time, to show both hallmarks of AD in vitro; A β plaques and neurofibrillary tangles, by combining cell genetic manipulation and fluorescence-activated cell sorting (FACS) selection of cells overexpressing the mutated genes. [103] Other research groups have also showed 3D in vitro cell culture models able to partially reproduce AD pathology. In one study, Zhang et al used human neuroepithelial-like stem cells (It-NES) in PuraMatrix hydrogel treated with synthetic A β , [104] and in another study, Choi et al exploited 3D neurospheroids from rat cells in a microfluidic platform treated with synthetic A β .…”