The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“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
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The HNO model has been shown to recapitulate some of the key pathological features of AD and offers greater complexity and translational potential as compared to conventional cell and animal models92–95.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [93]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Chen, Y., Wang, L., Kang, Q., Zhang, X., Yu, G., Wan, X., Wang, J., & Zhu, K. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000477308 · Cited by 10,730
Cerebral organoids model human brain development and microcephaly
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., & Knoblich, J. A. (2013) · Nature · doi:10.1038/nature12517 · Cited by 5,372
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051
Emerging roles of caspase-3 in apoptosis
Porter, A. G., & Jänicke, R. U. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400476 · Cited by 3,921
Organogenesis in a dish: Modeling development and disease using organoid technologies
Lancaster, M. A., & Knoblich, J. A. (2014) · Science · doi:10.1126/science.1247125 · Cited by 2,931
Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure
Qian, X., Nguyen, H. N., Song, M. M., Hadiono, C., Ogden, S. C., Hammack, C., Yao, B., Hamersky, G. R., Jacob, F., Zhong, C., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.032 · Cited by 2,127
Generation of cerebral organoids from human pluripotent stem cells
Lancaster, M. A., & Knoblich, J. A. (2014) · Nature Protocols · doi:10.1038/nprot.2014.158 · Cited by 1,823
Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., Hefferan, M. P., Van Gorp, S., Nazor, K. L., Boscolo, F. S., et al. (2012) · Nature · doi:10.1038/nature10821 · Cited by 1,253
A three-dimensional human neural cell culture model of Alzheimer’s disease
Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C., Chen, H., Hooli, B., Asselin, C., Muffat, J., et al. (2014) · Nature · doi:10.1038/nature13800 · Cited by 1,195
Zika virus impairs growth in human neurospheres and brain organoids
Garcez, P. P., Loiola, E. C., Madeiro da Costa, R., Higa, L. M., Trindade, P., Delvecchio, R., Nascimento, J. M., Brindeiro, R., Tanuri, A., & Rehen, S. K. (2016) · Science · doi:10.1126/science.aaf6116 · Cited by 1,184
Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H., & Younkin, S. G. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00372.2001 · Cited by 1,053
Induced pluripotency: history, mechanisms, and applicationsPreprint
Stadtfeld, M., & Hochedlinger, K. (2010) · Genes & Development · doi:10.1101/gad.1963910 · Cited by 857
Kondo, T., Asai, M., Tsukita, K., Kutoku, Y., Ohsawa, Y., Sunada, Y., Imamura, K., Egawa, N., Yahata, N., Okita, K., et al. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.01.009 · Cited by 741
Three dimensions of the amyloid hypothesis: time, space and 'wingmen'
Musiek, E. S., & Holtzman, D. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4018 · Cited by 662
Modeling familial Alzheimer's disease with induced pluripotent stem cells
Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., & Suzuki, N. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr394 · Cited by 599
Raja, W. K., Mungenast, A. E., Lin, Y.-T., Ko, T., Abdurrob, F., Seo, J., & Tsai, L.-H. (2016) · PLOS ONE · doi:10.1371/journal.pone.0161969 · Cited by 569
Klunk, W. E., Wang, Y., Huang, G.-F., Debnath, M. L., Holt, D. P., & Mathis, C. A. (2001) · Life Sciences · doi:10.1016/s0024-3205(01)01232-2 · Cited by 457
The hope and the hype of organoid research
Huch, M., Knoblich, J. A., Lutolf, M. P., & Martinez-Arias, A. (2017) · Development · doi:10.1242/dev.150201 · Cited by 409
Self‐organized developmental patterning and differentiation in cerebral organoids
Renner, M., Lancaster, M. A., Bian, S., Choi, H., Ku, T., Peer, A., Chung, K., & Knoblich, J. A. (2017) · The EMBO Journal · doi:10.15252/embj.201694700 · Cited by 389
Muratore, C. R., Rice, H. C., Srikanth, P., Callahan, D. G., Shin, T., Benjamin, L. N. P., Walsh, D. M., Selkoe, D. J., & Young-Pearse, T. L. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu064 · Cited by 379
Alzheimer disease models and human neuropathology: similarities and differences
Duyckaerts, C., Potier, M.-C., & Delatour, B. (2008) · Acta Neuropathologica · doi:10.1007/s00401-007-0312-8 · Cited by 375
A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome
Shi, Y., Kirwan, P., Smith, J., MacLean, G., Orkin, S. H., & Livesey, F. J. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003771 · Cited by 310
APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons.
Moore, S., Evans, L. D. B., Andersson, T., Portelius, E., Smith, J., Dias, T. B., Saurat, N., McGlade, A., Kirwan, P., Blennow, K., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.068 · Cited by 179
Zhang, D., Pekkanen-Mattila, M., Shahsavani, M., Falk, A., Teixeira, A. I., & Herland, A. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2013.11.028 · Cited by 171
Sproul, A. A., Jacob, S., Pre, D., Kim, S. H., Nestor, M. W., Navarro-Sobrino, M., Santa-Maria, I., Zimmer, M., Aubry, S., Steele, J. W., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084547 · Cited by 162
Mahairaki, V., Ryu, J., Peters, A., Chang, Q., Li, T., Park, T. S., Burridge, P. W., Talbot, C. C., Asnaghi, L., Martin, L. J., et al. (2014) · Stem Cells and Development · doi:10.1089/scd.2013.0511 · Cited by 120
Koch, P., Tamboli, I. Y., Mertens, J., Wunderlich, P., Ladewig, J., Stüber, K., Esselmann, H., Wiltfang, J., Brüstle, O., & Walter, J. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.02.012 · Cited by 115
Animal models of Alzheimer's disease and drug development
Laurijssens, B. E., Aujard, F., & Rahman, A. (2012) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2012.04.001 · Cited by 99
Armijo, E., González, C., Shahnawaz, M., Flores, A., Davis, B. R., & Soto, C. A. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.12.060 · Cited by 61
Self-citationHuman neural progenitors derived from integration-free iPSCs for SCI therapy
Liu, Y., Zheng, Y., Li, S., Xue, H., Schmitt, K., Hergenroeder, G. W., Wu, J., Zhang, Y., Kim, D., & Cao, Q. (2017) · Stem Cell Research · doi:10.1016/j.scr.2017.01.004 · Cited by 49
Isolation and Biochemical Characterization of Amyloid Plaques and Paired Helical Filaments
Rostagno, A. A., & Ghiso, J. A. (2009) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0333s44 · Cited by 44
Derivation of Induced Pluripotent Stem Cells by Lentiviral Transduction
Nethercott, H. E., Brick, D. J., & Schwartz, P. H. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-201-4_6 · Cited by 24
Cited by
Sorted by citations
Hofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988
Brain organoids: advances, applications and challenges
Qian, X., Song, H., & Ming, G.-L. (2019) · Development · doi:10.1242/dev.166074 · Cited by 724
Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output
Giandomenico, S. L., Mierau, S. B., Gibbons, G. M., Wenger, L. M. D., Masullo, L., Sit, T., Sutcliffe, M., Boulanger, J., Tripodi, M., Derivery, E., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0350-2 · Cited by 651
Modeling Alzheimer’s disease with iPSC-derived brain cells
Penney, J., Ralvenius, W. T., & Tsai, L.-H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0468-3 · Cited by 471
Metadata
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
