Modeling amyloid beta and tau pathology in human cerebral organoids

Abstract

The typical abnormalities observed in the brain of Alzheimer's disease (AD) patients include synaptic alterations, neuronal death, brain inflammation, and the accumulation of protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Despite the development of many animal and in vitro models for AD, there is a lack of an experimental approach that fully recapitulates essential aspects of the disease in human cells. Here, we report the generation of a new model to study AD, consisting of cerebral organoids (COs) produced from human-induced pluripotent stem cells (iPSCs). Under our experimental conditions, COs grow to form three-dimensional (3D) structures containing neural areas with cortical-like organization. Analysis of COs by histological and biochemical methods revealed that organoids produced from iPSCs derived from patients affected by familial AD or Down syndrome (DS) spontaneously develop over time pathological features of AD, including accumulation of structures highly reminiscent to amyloid plaques and neurofibrillary tangles. These pathological abnormalities were not observed in COs generated from various controls, including human iPSCs from healthy individuals, human iPSCs from patients affected by Creutzfeldt-Jakob disease, mouse embryonic stem cells (ESCs), or mouse iPSCs. These findings enable modeling genetic AD in a human cellular context in a 3D cortical-like tissue developed in vitro from patient-specific stem cells. This system provides a more relevant disease model compared to pre-existing methods and offers a new platform for discovery of novel targets and screening of drugs for therapeutic intervention.

“Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain”

“…We therefore hypothesized that organoids grown from some people with DS may develop AD-like pathology without any CRISPR-Cas9 intervention. Diffuse amyloid plaque-like appearance with Tau pathology was recently reported in 110 days old cerebral organoids from only a single DS-hiPSC line 45 so far.…”

Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms

“…One key aspect of hiPSCs that has made them so attractive for research and drug development is that the underlying patient genetics are retained, including pathological mutations [15,17]. This allows for in vitro modelling of the pathological phenotype via their differentiation to the affected cell types [18,19]. Further, organoids have enabled the characterization of disease in more complex cellular milieus and this is of great interest for drug screening in that they may allow movement away from animal models, and perhaps an accelerated, more effective drug screening process for an individual's disease [20,21].…”

Using brain organoids to study human neurodevelopment, evolution and disease

“…This method allows the manipulation of a small number of cells, which upon manipulation develop in a control environment. Abbreviations: iPSCs, induced pluripotent stem cells; CO, cerebral organoid; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; sgRNA, single guided RNA not possible, nevertheless the human patient genetic background is maintained, which is important in order to draw conclusions specific to an individual (Bershteyn et al, 2017;Gabriel et al, 2016;Gonzalez et al, 2018;. This could be particularly useful for multifactorial diseases where different unknown genetic variations can be causal, such as in patients with schizophrenia.…”