Modeling amyloid beta and tau pathology in human cerebral organoids

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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.

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Acknowledgements

We are grateful to Dr. Brian Davis (University of Texas Medical School at Houston) for his valuable help in establishing the iPSC technology in our lab, Dr. Fabrizio Tagliavini (Istituto Carlo Besta, Italy) for kindly providing human fibroblasts from patients affected by inherited Creutzfeldt–Jakob disease. We are also grateful to Dr. Ying Liu (Institute of Molecular Medicine, University of Texas at Houston) for providing an iPSC line obtained from healthy controls. This project was partially funded by a pilot grant from the University of Texas Brain Initiative Program.

Author contributions

CG designed the studies, carried out many of the experiments, analyzed the results, and prepared the first version of the figures. EA generated and characterized induced pluripotent stem cells used in these studies, performed some of the experiments and histological staining, analyzed some of the results, prepared the final version of the figures, and assisted in the preparation and writing of the final version of the manuscript. JB-A performed the biochemical studies to measure the levels of Aβ and tau aggregates. AB-C participated in the studies with mouse cerebral organoids. CM performed the western blot and ELISA studies of p-tau, generated induced pluripotent stem cells, produced the cerebral organoids derived from Creutzfeldt–Jakob disease cells, processed tissue samples, and assisted in the preparation and writing of the final version of the manuscript. CS is the principal investigator on the project and was responsible for coordinating research activity, analyzing the data, funding, writing the manuscript, and producing the final version of the article.

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Correspondence to Claudio Soto.

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Gonzalez, C., Armijo, E., Bravo-Alegria, J. et al. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23, 2363–2374 (2018) doi:10.1038/s41380-018-0229-8

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