Cited by 432Alzheimer's disease research and treatmentsPluripotent Stem Cells ResearchDementia and Cognitive Impairment Research

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Modeling amyloid beta and tau pathology in human cerebral organoids

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Gonzalez, Cesar, Armijo, Enrique, Bravo-Alegria, Javiera, Becerra-Calixto, Andrea, Mays, Charles E., Soto, Claudio·2018·Molecular Psychiatry

DOI 10.1038/s41380-018-0229-8PMC PMC6594704

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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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Authors: Gonzalez, C., Armijo, E., Bravo-Alegria, J., Becerra-Calixto, A., Mays, C. E., & Soto, C.
Affiliations: Universidad de Los Andes, Chile (CL)
Universidad de Antioquia (CO)
The University of Texas Health Science Center at Houston (US)
Corresponding author: Soto, Claudio
ORCID: Bravo-Alegria, Javiera
Becerra-Calixto, Andrea
Soto, Claudio
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2018-08-31
Volume: 23
Issue: 12
Pages: 2363-2374
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-018-0229-8
PMC: PMC6594704
OpenAlex: W2889449128
Cited by: 430
References: 33
Citations by year: 2026: 43 · 2025: 55 · 2024: 63 · 2023: 60 · 2022: 56 · 2021: 78 · 2020: 48 · 2019: 24 · 2018: 2
FWCI: 26.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (R01AG061069)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, brain organoids, amyloid plaques, neurofibrillary tangles, tau pathology, amyloid-beta, induced pluripotent stem cells, familial Alzheimer's disease, Down syndrome, patient-specific disease modeling, drug screening
MeSH terms: Aged, Alzheimer Disease, Brain, Cerebral Cortex, Female, Humans, Infant, Male, Middle Aged, Neurons, Organoids, Phosphorylation, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Cell Culture Techniques, Induced Pluripotent Stem Cells, Plaque, Amyloid

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Modeling amyloid beta and tau pathology in human cerebral organoids

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