A three-dimensional human neural cell culture model of Alzheimer’s disease
Open accessAbstract
Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.
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?
Beading or blebbing in neurites is a marker of dystrophic neurites in the AD brain.
“Beading or blebbing in neurites is a marker of dystrophic neurites in the AD brain (3, 42, 43).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [3]
The main text (page unavailable) describes beaded processes in the cultured cells as similar to dystrophic neurites found in AD brains, supporting the beading portion of the claim. It does not identify blebbing as a marker, and its observation is in a cell-culture model rather than directly in AD brain tissue. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn AD, tau protein becomes hyperphosphorylated, resulting in tau dissociating from microtubules and forming insoluble tau aggregates in the neurites and cell bodies.
“In AD, tau protein becomes hyperphosphorylated, resulting in tau dissociating from microtubules and forming insoluble tau aggregates in the neurites and cell bodies (3, 37).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [3]
The main text says tau is hyperphosphorylated in AD and reports insoluble p-tau aggregates in the cell bodies and neurite-like structures of its 3D culture model. It does not state that hyperphosphorylation causes tau to dissociate from microtubules, so that mechanistic step is unsupported by our copy. Page numbers are not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredModeling these pathological hallmarks has largely relied on transgenic cellular and animal models harboring genetic mutations linked to ADAD.
“Modeling these pathological hallmarks has largely relied on transgenic cellular and animal models harboring genetic mutations linked to ADAD (3–5).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [3]
Previous studies focused on overexpressing mutant APP and Presenilin in REN stem cells grown in a 3D culture, which differs from patient-specific LOAD model that relies on endogenous recapitulation of AD-associated phenotypes as provided in this study.
“As for human neurons, previous studies focused on overexpressing mutant APP and Presenilin in REN stem cells grown in a 3D culture (3), which differs from patient-specific LOAD model that relies on the endogenous recapitulation of AD-associated phenotypes as provided in this study.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [3]
Familial Alzheimer disease mutations in beta-amyloid precursor protein and presenilin 1 induced robust extracellular deposition of amyloid-beta in a human neural stem-cell-derived 3D culture system.
“one study revealed that familial AD (FAD) mutations in β-amyloid precursor protein and presenilin 1 induced robust extracellular deposition of amyloid-β in a human neural stem-cell-derived 3D culture system85.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [85]
3D-differentiated neuronal cells expressing familial Alzheimer disease mutations exhibited aggregates of phosphorylated tau and filamentous tau.
“the 3D-differentiated neuronal cells expressing FAD mutations exhibited aggregates of phosphorylated tau as well as filamentous tau.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [85]
A 3D in vitro culture of human iPSC-derived neurons overexpressing APP with FAD mutations generates robust Aβ42 production and amyloid deposition, and also develops elevated phospho-tau and fibrillary tau aggregates, suggesting elevated Aβ alone is sufficient to drive tau pathology in human neurons.
“A 3D in vitro culture system consisting of human neurons differentiated from induced pluripotent stem cells overexpressing human APP containing FAD mutations generates robust Aβ42 production and amyloid deposition. Importantly, this model also develops elevated phospho-tau levels and fibrillary tau aggregates, suggesting that elevated Aβ levels alone are sufficient to drive tau pathology in human”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Choi et al., 2014
Development of a 3D culture of human neural stem cells transfected with APPK670N/M671L/V717I and PS1ΔE9 in Matrigel scaffolding resulted in extracellular aggregation of Aβ into plaques and intracellular aggregation of tau in dystrophic neurites and the cell soma.
“It was recently shown that development of a 3D culture of human neural stem cells transfected with APPK670N/M671L/V717I and PS1ΔE9 in Matrigel scaffolding resulted in the extracellular aggregation of Aβ into plaques and the intracellular aggregation of tau in dystrophic neurites and the cell soma [23, 77].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [23]
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
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
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 · see citing works
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420 · see citing works
Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849 · see citing works
Self-citationProbing 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
GSK-3α regulates production of Alzheimer's disease amyloid-β peptides
Phiel, C. J., Wilson, C., Lee, V. M. ‐., & Klein, P. S. (2003) · Nature · doi:10.1038/nature01640 · Cited by 1,200 · 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
Cohen, R. M., Rezai-Zadeh, K. P., Weitz, T. M., Rentsendorj, A., Gate, D., Spivak, I. E., Bholat, Y., Vasilevko, V., Glabe, C. G., Breunig, J. J., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3672-12.2013 · Cited by 522 · see citing works
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 · see citing works
Donato, R., Miljan, E., Hines, S. J., Aouabdi, S., Pollock, K., Patel, S., Edwards, F. A., & Sinden, J. D. (2007) · BMC Neuroscience · doi:10.1186/1471-2202-8-36 · Cited by 308 · see citing works
Bioengineered functional brain-like cortical tissue
Tang‐Schomer, M. D., White, J. D., Tien, L. W., Schmitt, L. I., Valentin, T. M., Graziano, D. J., Hopkins, A. M., Omenetto, F. G., Haydon, P. G., & Kaplan, D. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1324214111 · Cited by 305 · see citing works
1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3β
Kunick, C., Lauenroth, K., Leost, M., Meijer, L., & Lemcke, T. (2003) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2003.10.062 · Cited by 180 · see citing works
Sproul, A. A., Jacob, S., Prè, D., Kim, S. H., Nestor, M. W., Navarro-Sobrino, M., Santa‐María, I., Zimmer, M., Aubry, S., Steele, J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084547 · Cited by 179 · see citing works
Neuronal and microglial involvement in beta-amyloid protein deposition in Alzheimer's disease.
Cras, P. P., Kawai, M., Siedlak, S. L., Mulvihill, P., Gambetti, P. L., Lowery, D. E., Gonzalez‐DeWhitt, P. A., Greenberg, B., & Perry, G. L. (1990) · Europe PMC (PubMed Central) · Cited by 174 · see citing works
[25] Use of excitatory amino acids to make axon-sparing lesions of hypothalamus
Nadler, J. V., & Evenson, D. A. (1983) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(83)03027-x · Cited by 149 · see citing works
Planel, E., Bretteville, A., Liu, L., Virág, L., Du, A. L., Yu, W. H., Dickson, D. W., Whittington, R. A., & Duff, K. (2009) · The FASEB Journal · doi:10.1096/fj.08-122424 · Cited by 138 · see citing works
3D Differentiation of Neural Stem Cells in Macroporous Photopolymerizable Hydrogel Scaffolds
Li, H., Wijekoon, A., & Leipzig, N. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048824 · Cited by 108 · see citing works
Selecting a Mouse Model of Alzheimer’s Disease
Chin, J. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-744-0_13 · Cited by 93 · see citing works
The role of tau in Alzheimer's disease
Trojanowski, J. Q., & Lee, V. M.-Y. (2002) · Medical Clinics of North America · doi:10.1016/s0025-7125(02)00002-0 · Cited by 85 · see citing works
GSK-3α/β kinases and amyloid production in vivo
Jaworski, T., Dewachter, I., Lechat, B., Gees, M., Kremer, A., Demedts, D., Borghgraef, P., Devijver, H., Kügler, S., Patel, S., et al. (2011) · Nature · doi:10.1038/nature10615 · Cited by 69 · see citing works
Wagner, S. L., Zhang, C. M., Cheng, S., Nguyen, P. A. H., Zhang, X., Rynearson, K. D., Wang, R., Li, Y., Sisodia, S. S., Mobley, W. C., et al. (2014) · Biochemistry · doi:10.1021/bi401537v · Cited by 50 · see citing works
Self-citationKirby, L. A., Schott, J. T., Noble, B. L., Mendez, D. C., Caseley, P. S., Peterson, S. C., Routledge, T. J., & Patel, N. V. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039329 · Cited by 49 · see citing works
Mazemondet, O., Hübner, R., Frahm, J., Koczan, D., Bader, B., Weiss, D. G., Uhrmacher, A. M., Frech, M. J., Rolfs, A., & Luo, J. (2011) · Cellular & Molecular Biology Letters · doi:10.2478/s11658-011-0021-0 · Cited by 40 · see citing works
Human stem cell-derived neurons: a system to study human tau function and dysfunction
Iovino, M., Patani, R., Watts, C., Chandran, S., & Spillantini, M. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013947 · Cited by 40 · see citing works
Biochemical Isolation of Insoluble Tau in Transgenic Mouse Models of Tauopathies
Julien, C., Bretteville, A., & Planel, E. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-551-0_32 · Cited by 36 · see citing works
Transgenic mouse models of Alzheimer's disease: phenotype and mechanisms of pathogenesis
Duff, K. (2001) · Biochemical Society Symposia · doi:10.1042/bss0670195 · Cited by 26 · see citing works
Use of Excitatory Amino Acids to Make Axon-Sparing Lesions of Hypothalamus
Nadler, J. V., & Evenson, D. A. (1989) · Elsevier eBooks · doi:10.1016/b978-0-12-185150-7.50060-9 · Cited by 25 · see citing works
iPSCs to the Rescue in Alzheimer's Research
Choi, S. H., & Tanzi, R. E. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.02.011 · Cited by 23 · see citing works
Self-citationProtection of neurons derived from human neural progenitor cells by veratridine
Morgan, P. J., Ortinau, S., Frahm, J., Krüger, N., Rolfs, A., & Frech, M. J. (2009) · Neuroreport · doi:10.1097/wnr.0b013e32832fbf49 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Scheltens, P., Blennow, K., Breteler, M. M. B., de Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01124-1 · Cited by 3,125 · see citing works
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952 · see citing works
Microglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767 · see citing works
Exosome Theranostics: Biology and Translational Medicine
He, C., Zheng, S., Luo, Y., & Wang, B. (2017) · Theranostics · doi:10.7150/thno.21945 · Cited by 1,259 · see citing works
Synergy between amyloid-β and tau in Alzheimer’s disease
Busche, M. A., & Hyman, B. T. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0687-6 · Cited by 1,242 · see citing works
Hofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184 · see citing works
Goedert, M. (2015) · Science · doi:10.1126/science.1255555 · Cited by 977 · see citing works
Alzheimer's disease: experimental models and reality
Drummond, E., & Wisniewski, T. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1662-x · Cited by 810 · see citing works
Choi, S. H., Bylykbashi, E., Chatila, Z. K., Lee, S. W., Pulli, B., Clemenson, G. D., Kim, E., Rompala, A., Oram, M. K., Asselin, C., et al. (2018) · Science · doi:10.1126/science.aan8821 · Cited by 802 · see citing works
Self-citationThe use of brain organoids to investigate neural development and disease
Di Lullo, E., & Kriegstein, A. R. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.107 · Cited by 788 · see citing works
The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials
Sperling, R., Mormino, E., & Johnson, K. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.038 · Cited by 725 · see citing works
A decade of progress in tissue engineering
Khademhosseini, A., & Langer, R. (2016) · Nature Protocols · doi:10.1038/nprot.2016.123 · Cited by 746 · see citing works
Brain organoids: advances, applications and challenges
Qian, X., Song, H., & Ming, G.-L. (2019) · Development · doi:10.1242/dev.166074 · Cited by 724 · see citing works
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 697 · see citing works
Eimer, W. A., Vijaya Kumar, D. K., Navalpur Shanmugam, N. K., Rodriguez, A. S., Mitchell, T., Washicosky, K. J., György, B., Breakefield, X. O., Tanzi, R. E., & Moir, R. D. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.030 · Cited by 674 · see citing works
Self-citationMinter, M. R., Zhang, C., Leone, V., Ringus, D. L., Zhang, X., Oyler-Castrillo, P., Musch, M. W., Liao, F., Ward, J. F., Holtzman, D. M., et al. (2016) · Scientific Reports · doi:10.1038/srep30028 · Cited by 655 · see citing works
Self-citationA 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease
Park, J., Wetzel, I., Marriott, I., Dréau, D., D’Avanzo, C., Kim, D. Y., Tanzi, R. E., & Cho, H. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0175-4 · Cited by 644 · see citing works
Self-citationAmyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.014 · Cited by 575 · see citing works
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
The probabilistic model of Alzheimer disease: the amyloid hypothesis revised
Frisoni, G. B., Altomare, D., Thal, D. R., Ribaldi, F., van der Kant, R., Ossenkoppele, R., Blennow, K., Cummings, J., van Duijn, C., Nilsson, P. M., et al. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00533-w · Cited by 513 · see citing works
The rise of three-dimensional human brain cultures
Pașca, S. P. (2018) · Nature · doi:10.1038/nature25032 · Cited by 509 · see citing works
Organotypic brain slice cultures: A review
Humpel, C. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.086 · Cited by 480 · see citing works
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 · see citing works
Guo, L. E., Kim, H. J., Wang, H. H., Monaghan, J., Freyermuth, F., Sung, J. C., O’Donovan, K., Fare, C. M., Diaz, Z., Singh, N., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.002 · Cited by 467 · see citing works
Wu, T., Dejanovic, B., Gandham, V. D., Gogineni, A., Edmonds, R., Schauer, S., Srinivasan, K., Huntley, M. A., Wang, Y., Wang, T.-M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.060 · Cited by 466 · see citing works
Drug development in Alzheimer’s disease: the path to 2025
Cummings, J., Aisen, P. S., DuBois, B., Frölich, L., Jack, C. R., Jones, R. W., Morris, J. C., Raskin, J., Dowsett, S. A., & Scheltens, P. (2016) · Alzheimer's Research & Therapy · doi:10.1186/s13195-016-0207-9 · Cited by 459 · see citing works
The antimicrobial protection hypothesis of Alzheimer’s disease
Moir, R. D., Lathe, R., & Tanzi, R. E. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.06.3040 · Cited by 456 · see citing works
Self-citationInteractions of pathological proteins in neurodegenerative diseases
Spires‐Jones, T. L., Attems, J., & Thal, D. R. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1709-7 · Cited by 424 · see citing works
Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony
Forner, S., Baglietto-Vargas, D., Martini, A. C., Trujillo-Estrada, L., & LaFerla, F. M. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.04.002 · Cited by 430 · see citing works
Modeling 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
Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro
Bardy, C., van den Hurk, M., Eames, T., Marchand, C., Hernandez, R. V., Kellogg, M., Gorris, M., Galet, B., Palomares, V., Brown, J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504393112 · Cited by 428 · see citing works
Targa Dias Anastacio, H., Matosin, N., & Ooi, L. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02024-7 · Cited by 401 · see citing works
Rodent models for Alzheimer disease
Götz, J., Bodea, L., & Goedert, M. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0054-8 · Cited by 397 · see citing works
Volpato, V., & Webber, C. (2020) · Disease Models & Mechanisms · doi:10.1242/dmm.042317 · Cited by 379 · see citing works
The complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J. D., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 374 · see citing works
Zhao, J., Fu, Y., Yamazaki, Y., Ren, Y., Davis, M. D., Liu, C.-C., Lu, W., Wang, X., Chen, K., Cherukuri, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19264-0 · Cited by 374 · see citing works
Ferreira, S. T., Lourenco, M. V., Oliveira, M. M., & De Felice, F. G. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00191 · Cited by 373 · see citing works
Induced Pluripotent Stem Cells and Their Use in Human Models of Disease and Development
Karagiannis, P., Takahashi, K., Saito, M. K., Yoshida, Y., Okita, K., Watanabe, A., Inoue, H., Yamashita, J. K., Todani, M., Nakagawa, M., et al. (2018) · Physiological Reviews · doi:10.1152/physrev.00039.2017 · Cited by 367 · see citing works
McQuade, A., Kang, Y. J., Hasselmann, J., Jairaman, A., Sotelo, A., Coburn, M., Shabestari, S. K., Chadarevian, J. P., Fote, G., Tu, C. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19227-5 · Cited by 361 · see citing works
van der Kant, R., Langness, V. F., Herrera, C. M., Williams, D. A., Fong, L. K., Leestemaker, Y., Steenvoorden, E., Rynearson, K. D., Brouwers, J. F., Helms, J. B., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.12.013 · Cited by 350 · see citing works
Self-citationModeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids
Kim, H., Park, H. J., Choi, H. G., Chang, Y., Park, H., Shin, J., Kim, J., Lengner, C. J., Lee, Y. K., & Kim, J. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.01.020 · Cited by 352 · see citing works
PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease
Oksanen, M., Petersen, A. J., Naumenko, N., Puttonen, K., Lehtonen, Š., Gubert Olivé, M., Shakirzyanova, A., Leskelä, S., Sarajärvi, T., Viitanen, M., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.016 · Cited by 332 · see citing works
Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
McAlpine, C. S., Park, J., Griciuc, A., Kim, E., Choi, S. H., Iwamoto, Y., Kiss, M. G., Christie, K. A., Vinegoni, C., Poller, W. C., et al. (2021) · Nature · doi:10.1038/s41586-021-03734-6 · Cited by 322 · see citing works
Self-citationBuilding Models of Brain Disorders with Three-Dimensional Organoids
Amin, N. D., & Paşca, S. P. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.007 · Cited by 312 · see citing works
3D Printed Stem‐Cell Derived Neural Progenitors Generate Spinal Cord Scaffolds
Joung, D., Truong, V., Neitzke, C. C., Guo, S., Walsh, P., Monat, J. R., Meng, F., Park, S. H., Dutton, J. R., Parr, A. M., et al. (2018) · Advanced Functional Materials · doi:10.1002/adfm.201801850 · Cited by 308 · see citing works
Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans
Saykin, A. J., Shen, L., Yao, X., Kim, S., Nho, K. T., Risacher, S. L., Ramanan, V. K., Foroud, T., Faber, K. M., Sarwar, N., et al. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.05.009 · Cited by 301 · see citing works
Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease
Villegas, S., Roda, A., Serra-Mir, G., Montoliu-Gaya, L., & Tiessler, L. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.332127 · Cited by 306 · see citing works
Human cerebral organoids — a new tool for clinical neurology research
Eichmüller, O. L., & Knoblich, J. A. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00723-9 · Cited by 260 · see citing works
Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes
Cummings, J. (2018) · Clinical and Translational Science · doi:10.1111/cts.12491 · Cited by 298 · see citing works
Inhibition of protein aggregation and amyloid formation by small molecules
Doig, A. J., & Derreumaux, P. (2015) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2014.12.004 · Cited by 295 · see citing works
Minter, M. R., Hinterleitner, R., Meisel, M., Zhang, C., Leone, V., Zhang, X., Oyler-Castrillo, P., Zhang, X., Musch, M. W., Shen, X., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-11047-w · Cited by 292 · see citing works
Self-citationIn vitro Models of Neurodegenerative Diseases
Slanzi, A., Iannoto, G., Rossi, B., Zenaro, E., & Constantin, G. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00328 · Cited by 293 · see citing works
Ma, Q., Zhao, Z., Sagare, A. P., Wu, Y., Wang, M., Owens, N. C., Verghese, P. B., Herz, J., Holtzman, D. M., & Zlokovic, B. V. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0286-0 · Cited by 281 · see citing works
Chun, H., Im, H., Kang, Y. J., Kim, Y., Shin, J. H., Won, W., Lim, J., Ju, Y. H., Park, Y. M., Kim, S., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-00735-y · Cited by 274 · see citing works
Self-citationClearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 275 · see citing works
Therriault, J., Vermeiren, M. R., Servaes, S., Tissot, C., Ashton, N. J., Benedet, A. L., Karikari, T. K., Lantero‐Rodriguez, J., Brum, W. S., Lussier, F. Z., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.4485 · Cited by 268 · see citing works
Blood–Brain Barrier Dysfunction in a 3D In Vitro Model of Alzheimer's Disease
Shin, Y., Choi, S.-H., Kim, E., Bylykbashi, E., Kim, J. A., Chung, S., Kim, D. Y., Kamm, R., & Tanzi, R. (2019) · Advancement of science · doi:10.1002/advs.201900962 · Cited by 244 · see citing works
Self-citationTau-based therapies in neurodegeneration: opportunities and challenges
Li, C., & Götz, J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.155 · Cited by 272 · see citing works
3D neural tissue models: From spheroids to bioprinting
Zhuang, P., Sun, A. X., An, J., Chua, C. K., & Chew, S. Y. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.10.002 · Cited by 269 · 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
Self-citationCenteno, E. G. Z., Cimarosti, H., & Bithell, A. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0258-4 · Cited by 268 · see citing works
The Evolution of Polystyrene as a Cell Culture Material
Lerman, M. J., Lembong, J., Muramoto, S., Gillen, G. J., & Fisher, J. P. (2018) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2018.0056 · Cited by 261 · see citing works
Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism
Stancu, I.-C., Vasconcelos, B., Terwel, D., & Dewachter, I. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-51 · Cited by 256 · see citing works
Challenges of Organoid Research
Andrews, M., & Kriegstein, A. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-111020-090812 · Cited by 216 · see citing works
McMurtrey, R. J. (2015) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2015.0375 · Cited by 248 · see citing works
A 3D human brain–like tissue model of herpes-induced Alzheimer’s disease
Cairns, D. M., Rouleau, N., Parker, R. N., Walsh, K. G., Gehrke, L., & Kaplan, D. L. (2020) · Science Advances · doi:10.1126/sciadv.aay8828 · Cited by 247 · see citing works
Propagation of prions causing synucleinopathies in cultured cells
Woerman, A. L., Stöhr, J., Aoyagi, A., Rampersaud, R., Krejciova, Z., Watts, J. C., Ohyama, T., Patel, S. S., Widjaja, K., Oehler, A., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1513426112 · Cited by 241 · see citing works
de Medeiros, L. M., Bastiani, M. A. D., Rico, E. P., Schönhofen, P., Pfaffenseller, B., Wollenhaupt-Aguiar, B., Grün, L. K., Barbé‐Tuana, F. M., Zimmer, E. R., Castro, M. A. A., et al. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1605-3 · Cited by 247 · see citing works
Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain
Espuny-Camacho, I., Arranz, A. M., Fiers, M., Snellinx, A., Ando, K., Munck, S., Bonnefont, J., Lambot, L., Corthout, N., Omodho, L., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.001 · Cited by 244 · see citing works
Ghatak, S., Dolatabadi, N., Trudler, D., Zhang, X., Wu, Y., Mohata, M., Ambasudhan, R., Talantova, M., & Lipton, S. A. (2019) · eLife · doi:10.7554/elife.50333 · Cited by 227 · see citing works
Walking the tightrope: proteostasis and neurodegenerative disease
Yerbury, J. J., Ooi, L., Dillin, A. G., Saunders, D. N., Hatters, D. M., Beart, P. M., Cashman, N. R., Wilson, M. R., & Ecroyd, H. W. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13575 · Cited by 243 · see citing works
MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease
Balusu, S., Horré, K., Thrupp, N., Craessaerts, K., Snellinx, A., Serneels, L., T’Syen, D., Chrysidou, I., Arranz, A. M., Sierksma, A. S. R., et al. (2023) · Science · doi:10.1126/science.abp9556 · Cited by 234 · see citing works
Zhang, X., Tian, Y., Zhang, C. M., Tian, X., Ross, A., Moir, R. D., Sun, H., Tanzi, R. E., Moore, A. V., & Ran, C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505420112 · Cited by 227 · see citing works
Self-citationBioengineering Approaches for the Advanced Organoid Research
Yi, S. A., Zhang, Y., Rathnam, C., Pongkulapa, T., & Lee, K. (2021) · Advanced Materials · doi:10.1002/adma.202007949 · Cited by 218 · see citing works
Park, J., Jang, S., Lee, D., Lee, J.-H., Kang, U., Chang, H., Kim, H. J., Han, S.-H., Seo, J., Choi, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20440-5 · Cited by 224 · see citing works
Jorfi, M., Park, J., Hall, C. K., Lin, C.-C. J., Chen, M., von Maydell, D., Kruskop, J. M., Kang, B., Choi, Y., Prokopenko, D., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01415-3 · Cited by 214 · see citing works
Self-citationAdvancement in the modelling and therapeutics of Parkinson’s disease
Nand, S., & Singh, P. (2020) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2020.101752 · Cited by 213 · see citing works
Bal‐Price, A. (2018) · ALTEX · doi:10.14573/altex.1712081 · Cited by 211 · see citing works
Updates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 220 · see citing works
iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders
Okano, H., & Morimoto, S. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.01.007 · Cited by 203 · see citing works
Developing predictive assays: The phenotypic screening “rule of 3”
Vincent, F., Loria, P. M., Pregel, M. J., Stanton, R. V., Kitching, L., Nocka, K. H., Doyonnas, R., Steppan, C. M., Gilbert, A. M., Schroeter, T., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aab1201 · Cited by 200 · see citing works
Rosato, A. S., Montefusco, S., Soldati, C., Paola, S. D., Capuozzo, A., Monfregola, J., Polishchuk, E., Amabile, A., Grimm, C. M., Lombardo, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13572-w · Cited by 199 · see citing works
Bioprinting towards physiologically relevant tissue models for pharmaceutics
Peng, W., Unutmaz, D., & Ozbolat, I. T. (2016) · Trends in Biotechnology · doi:10.1016/j.tibtech.2016.05.013 · Cited by 196 · see citing works
Lee, C., Bendriem, R. M., Wu, W. W., & Shen, R. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0362-8 · Cited by 198 · see citing works
Vasconcelos, B., Stancu, I.-C., Buist, A., Bird, M., Wang, P., Vanoosthuyse, A., Van Kolen, K., Verheyen, A., Kienlen-Campard, P., Octave, J.-N., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1525-x · Cited by 192 · see citing works
Lee, H.-K., Velazquez Sanchez, C., Chen, M., Morin, P. J., Wells, J. M., Hanlon, E. B., & Xia, W. (2016) · PLOS ONE · doi:10.1371/journal.pone.0163072 · Cited by 190 · see citing works
Functionalization of Brain Region-specific Spheroids with Isogenic Microglia-like Cells
Song, L., Yuan, X., Jones, Z., Vied, C., Yu, M., Marzano, M., Hua, T., Sang, Q. A., Guan, J., Ma, T., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47444-6 · Cited by 186 · see citing works
Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact
Moretti, R., Morelli, M. E., & Caruso, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082245 · Cited by 190 · see citing works
Sabaté‐Soler, S., Nickels, S., Saraiva, C., Berger, E., Dubonyte, U., Barmpa, K., Lan, Y. J., Kouno, T., Jarazo, J., Robertson, G., et al. (2022) · Glia · doi:10.1002/glia.24167 · Cited by 191 · see citing works
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 · see citing works
Cummings, J., Ritter, A., & Zhong, K. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179901 · Cited by 176 · see citing works
Modeling Neurological Diseases With Human Brain Organoids
Wang, H. (2018) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2018.00015 · Cited by 172 · see citing works
Clinical strategies and animal models for developing senolytic agents
Kirkland, J. L., & Tchkonia, T. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2014.10.012 · Cited by 168 · see citing works
Mazzocchi, A. R., Söker, S., & Skardal, A. (2019) · Applied Physics Reviews · doi:10.1063/1.5056188 · Cited by 174 · see citing works
Lab-on-chip technology for chronic disease diagnosis
Wu, J., Dong, M., Rigatto, C., Liu, Y., & Lin, F. (2018) · npj Digital Medicine · doi:10.1038/s41746-017-0014-0 · Cited by 170 · see citing works
Dissociating Normal Aging from Alzheimer’s Disease: A View from Cognitive Neuroscience
Toepper, M. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161099 · Cited by 166 · see citing works
Compound-based Chinese medicine formula: From discovery to compatibility mechanism
Luan, X., Zhang, L., Li, X., Rahman, K., Zhang, H., Chen, H., & Zhang, W. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.112687 · Cited by 169 · see citing works
Self-citation
- Authors
- Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C., Chen, H., Hooli, B., Asselin, C., Muffat, J., Klee, J. B., Zhang, C., Wainger, B. J., Peitz, M., Kovacs, D. M., Woolf, C. J., Wagner, S. L., Tanzi, R. E., & Kim, D. Y.
- Affiliations
- Harvard University (US)
- University of Bonn (DE)
- Boston Children's Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- University of California San Diego (US)
- Corresponding author
- Tanzi, Rudolph E.
- Kim, Doo Yeon
- ORCID
- Venue
- Nature
- Published
- 2014-10-12
- Volume
- 515
- Issue
- 7526
- Pages
- 274-278
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4366007
- OpenAlex
- W2126231259
- Cited by
- 1,195
- References
- 30
- Citations by year
- 2026: 67 · 2025: 75 · 2024: 95 · 2023: 88 · 2022: 112 · 2021: 111 · 2020: 141 · 2019: 109 · 2018: 109 · 2017: 87 · 2016: 97 · 2015: 87 · 2014: 14 · 2012: 1
- FWCI
- 63.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Massachusetts General Hospital
- Cure Alzheimer's Fund
- University of Edinburgh
- National Institute on Aging (5P01 AG15379, P01AG015379, R21AG031483, RF1AG048080, P50AG005134, R01AG014713, P01AG004953, P30AG062421)
- National Institute of Mental Health (R37MH060009)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, P30DK043351)
- National Institute of Neurological Disorders and Stroke (P30NS045776, R01NS045860)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, familial Alzheimer's disease, amyloid plaques, tauopathy, neurofibrillary tangles, amyloid hypothesis, presenilin 1 mutations, human neural stem cells, 3D cell culture, human neurons, beta-secretase inhibition, gamma-secretase inhibition, tau phosphorylation, drug screening model
- MeSH terms
- Alzheimer Disease, Cell Differentiation, Drug Evaluation, Preclinical, Extracellular Space, Humans, Microtubule-Associated Proteins, Models, Biological, Phosphorylation, Reproducibility of Results, Amyloid beta-Peptides, Neurites, tau Proteins, Cell Culture Techniques, Glycogen Synthase Kinase 3, Presenilin-1, Neural Stem Cells, Protein Aggregation, Pathological
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
