A 3D Alzheimer's disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons
Open accessAbstract
The recent progress in stem cell techniques has broadened the horizon for in vitro disease modeling. For desired in vivo like phenotypes, not only correct cell type specification will be critical, the microenvironmental context will be essential to achieve relevant responses. We demonstrate how a three dimensional (3D) culture of stem cell derived neurons can induce in vivo like responses related to Alzheimer's disease, not recapitulated with conventional 2D cultures. To acquire a neural population of cells we differentiated neurons from neuroepithelial stem cells, derived from induced pluripotent stem cells. p21-activated kinase mediated sensing of Aβ oligomers was only possible in the 3D environment. Further, the 3D phenotype showed clear effects on F-actin associated proteins, connected to the disease processes. We propose that the 3D in vitro model has higher resemblance to the AD pathology than conventional 2D cultures and could be used in further studies of the disease.
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
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?
Both the activation and localization patterns of the p21-activated kinase are characteristic of neurons in an Alzheimer's disease state.
“Both the activation and localization patterns of the p21-activated kinase are characteristic of neurons in an Alzheimer’s disease state.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [196]
The corresponding 2D culture did not show this activation and localization, suggesting that the 3D organoid culture of neurons is critical for modeling Alzheimer's disease.
“In contrast, the corresponding 2D culture did not show this activation and localization, suggesting that the 3D organoid culture of neurons is critical for modeling Alzheimer’s disease196.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [196]
A 3D culture in RADA-16 resulted in activation of a p21-activated kinase in response to amyloid-β oligomers.
“A 3D culture in RADA-16 resulted in activation of a p21-activated kinase in response to amyloid-β oligomers.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [196]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
Matrix elasticity directs stem cell lineage specification
Engler, A. J., Sen, S., Sweeney, H. L., & Discher, D. E. (2006) · Cell · doi:10.1016/j.cell.2006.06.044 · Cited by 13,915 · see citing works
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569 · see citing works
Taking Cell-Matrix Adhesions to the Third Dimension
Cukierman, E., Pankov, R., Stevens, D. R., & Yamada, K. M. (2001) · Science · doi:10.1126/science.1064829 · Cited by 3,027 · see citing works
Variant of <i>TREM2</i> Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · see citing works
Modeling Tissue Morphogenesis and Cancer in 3D
Yamada, K. M., & Cukierman, E. (2007) · Cell · doi:10.1016/j.cell.2007.08.006 · Cited by 1,751 · see citing works
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 · see citing works
Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds
Holmes, T. C., Lacalle, S. D., Su, X., Liu, G., Rich, A., & Zhang, S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.12.6728 · Cited by 1,124 · see citing works
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 · see citing works
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 · see citing works
Koutsopoulos, S., Unsworth, L. D., Nagai, Y., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807506106 · Cited by 476 · see citing works
Alzheimer disease models and human neuropathology: similarities and differences
Duyckaerts, C. J., Potier, M., & Delatour, B. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0312-8 · Cited by 441 · see citing works
Falk, A., Koch, P., Kesavan, J., Takashima, Y., Ladewig, J., Alexander, M., Wiskow, O., Tailor, J. K., Trotter, M. W. B., Pollard, S. M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029597 · Cited by 325 · see citing works
Self-citationRole of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease
Zhao, L., Ma, Q.-L., Calon, F., Harris-White, M. E., Yang, F., Lim, G. P., Morihara, T., Ubeda, O. J., Ambegaokar, S., Hansen, J. E., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1630 · Cited by 317 · see citing works
Mechanics in Neuronal Development and Repair
Franze, K., Janmey, P. A., & Guck, J. R. (2013) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071811-150045 · Cited by 310 · see citing works
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 · see citing works
ADF/cofilin and actin dynamics in disease
Bamburg, J. R., & Wiggan, O. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)02404-2 · Cited by 287 · see citing works
A tension-induced mechanotransduction pathway promotes epithelial morphogenesis
Zhang, H., Landmann, F., Fahs, H. Z., Rodriguez, D., Koch, M., & Labouesse, M. (2011) · Nature · doi:10.1038/nature09765 · Cited by 280 · see citing works
Geraldo, S., Khanzada, U. K., Parsons, M., Chilton, J. K., & Gordon‐Weeks, P. R. (2008) · Nature Cell Biology · doi:10.1038/ncb1778 · Cited by 242 · see citing works
The promotion of neuronal maturation on soft substrates
Teixeira, A. I., Ilkhanizadeh, S., Wigenius, J. A., Duckworth, J. K., Inganäs, O., & Hermanson, O. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.05.013 · Cited by 187 · see citing works
Self-citationShim, K. S., & Lübec, G. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00210-0 · Cited by 186 · see citing works
Dynamic Microenvironments: The Fourth Dimension
Tibbitt, M. W., & Anseth, K. S. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004804 · Cited by 169 · see citing works
p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis
Ma, Q., Yang, F., Calon, F., Ubeda, O. J., Hansen, J. E., Weisbart, R. H., Beech, W. K., Frautschy, S. A., & Cole, G. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708034200 · Cited by 130 · see citing works
Choi, Y. J., Park, J.-S., & Lee, S. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.01.038 · Cited by 106 · see citing works
PAK in Alzheimer disease, Huntington disease and X-linked mental retardation
Ma, Q., Yang, F., Frautschy, S. A., & Cole, G. M. (2012) · Cellular Logistics · doi:10.4161/cl.21602 · Cited by 85 · see citing works
Nikolić, M. (2008) · Molecular Neurobiology · doi:10.1007/s12035-008-8032-1 · Cited by 56 · see citing works
Mendoza‐Naranjo, A., Contreras-Vallejos, E., Henríquez, D. R., Carola Otth, L., Bamburg, J. R., Maccioni, R. B., & González-Billault, C. E. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-101575 · Cited by 51 · see citing works
Three-dimensional growth matrix for human embryonic stem cell-derived neuronal cells
Ylä‐Outinen, L., Joki, T., Varjola, M., et al. (2012) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.1512 · Cited by 48 · see citing works
Seidel, D., Krinke, D., Jahnke, H., Hirche, A., Kloß, D., Mack, T. G. A., Striggow, F., & Robitzki, A. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049150 · Cited by 46 · see citing works
Warr, M. R., & Passegue, E. A. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.12.005 · Cited by 43 · see citing works
Peptide- and collagen-based hydrogel substrates for in vitro culture of chick cochleae
Spencer, N. J., Cotanche, D. A., & Klapperich, C. M. (2007) · Biomaterials · doi:10.1016/j.biomaterials.2007.11.006 · Cited by 31 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
Engineered In Vitro Disease Models
Benam, K. H., Dauth, S., Hassell, B., Herland, A., Jain, A., Jang, K.-J., Karalis, K., Kim, H. J., MacQueen, L., Mahmoodian, R., et al. (2015) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040418 · Cited by 554 · see citing works
Self-citationModeling amyloid beta and tau pathology in human cerebral organoids
Gonzalez, C., Armijo, E., Bravo-Alegria, J., Becerra-Calixto, A., Mays, C. E., & Soto, C. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0229-8 · Cited by 430 · see citing works
Towards organoid culture without Matrigel
Kozlowski, M. T., Crook, C. J., & Ku, H. T. (2021) · Communications Biology · doi:10.1038/s42003-021-02910-8 · Cited by 409 · see citing works
Centeno, E. G. Z., Cimarosti, H., & Bithell, A. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0258-4 · Cited by 268 · see citing works
A 3D human neural cell culture system for modeling Alzheimer's disease
Kim, Y. H., Choi, S. H., D'Avanzo, C., Hebisch, M., Sliwinski, C., Bylykbashi, E., Washicosky, K. J., Klee, J. B., Brüstle, O., Tanzi, R. E., et al. (2015) · Nature Protocols · doi:10.1038/nprot.2015.065 · Cited by 269 · see citing works
Candiello, J., Grandhi, T. S. P., Goh, S. K., Vaidya, V., Lemmon-Kishi, M., Eliato, K. R., Ros, R., Kumta, P. N., Rege, K., & Banerjee, I. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.05.031 · Cited by 146 · see citing works
Stem cell models of Alzheimer’s disease: progress and challenges
Arber, C., Lovejoy, C., & Wray, S. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0268-4 · Cited by 143 · see citing works
Papadimitriou, C., Celikkaya, H., Cosacak, M. I., Mashkaryan, V., Bray, L., Bhattarai, P., Brandt, K., Hollak, H., Chen, X., He, S., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.06.005 · Cited by 143 · see citing works
Amyloid-β oligomers in cellular models of Alzheimer’s disease
Fontana, I. C., Zimmer, A. R., Rocha, A. S., Gosmann, G., Souza, D. O., Lourenco, M. V., Ferreira, S. T., & Zimmer, E. R. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15030 · Cited by 115 · see citing works
Ovadia, E. M., Colby, D. W., & Kloxin, A. M. (2018) · Biomaterials Science · doi:10.1039/c8bm00099a · Cited by 40 · see citing works
- Authors
- Zhang, D., Pekkanen-Mattila, M., Shahsavani, M., Falk, A., Teixeira, A. I., & Herland, A.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Herland, Anna
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 35
- Issue
- 5
- Pages
- 1420-1428
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2087507743
- Cited by
- 171
- References
- 31
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 6 · 2023: 11 · 2022: 14 · 2021: 16 · 2020: 25 · 2019: 18 · 2018: 19 · 2017: 14 · 2016: 19 · 2015: 10 · 2014: 7 · 2013: 1
- FWCI
- 8.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biomaterials (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Swedish Research Council
- AstraZeneca
- Vinnova
- Forska utan Djurförsök
- Ki Fonder
- Foundation for Geriatric Diseases at Karolinska Institutet
- StratNeuro
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Alzheimer's disease, 3D culture models, iPSC-derived neurons, neuroepithelial stem cells, p21-activated kinase, amyloid-beta oligomers, F-actin, microenvironment, in vitro disease model
- MeSH terms
- Alzheimer Disease, Cell Differentiation, Cells, Cultured, Fluorescent Antibody Technique, Humans, Models, Biological, Neurons, Amyloid beta-Peptides, p21-Activated Kinases, Induced Pluripotent Stem Cells, Real-Time Polymerase Chain Reaction
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
