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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.
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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In iPSC-derived neurons from both FAD- and SAD-patients, pTau aberrantly accumulates at early time points (Choi et al., 2014, Israel et al., 2012, Moore et al., 2015, Muratore et al., 2014, Ochalek et al., 2017, Shi et al., 2012).”
From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Choi et al., 2014
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“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]
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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
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Metadata
- 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
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
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