Modeling amyloid beta and tau pathology in human cerebral organoids
Open accessAbstract
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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iPSC-based models derived from individuals with a MAPT mutation indicate molecular mechanisms underlying tauopathies.
“Despite this limitation, iPSC-based models derived from individuals with a MAPT mutation indicate molecular mechanisms underlying tauopathies (Gonzalez et al., 2018; lovino et al., 2015; Jiang et al., 2018; Nakamura et al., 2019; Silva et al., 2016, 2020; Wray, 2017).”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Gonzalez et al., 2018
The Results identify the patient-derived iPSC model as familial Alzheimer’s disease with a presenilin 1 mutation and Down syndrome, not a MAPT mutation. The Discussion explicitly says tau developed a pathological phenotype in these organoids “without any mutations in the tau gene.” No page number is available in our copy. (LLM, conf=0.88)
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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
- Venue
- Molecular Psychiatry
- Published
- 2018-08-31
- Volume
- 23
- Issue
- 12
- Pages
- 2363-2374
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- 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
- Health Sciences › Medicine › Physiology › 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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