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A three-dimensional human neural cell culture model of Alzheimer's disease.

Abstract

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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  • Authors+Show Affiliations

    ,

    1] Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA [2].

    ,

    1] Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA [2] Division of Mass Spectrometry Research, Korea Basic Science Institute, Cheongju-si, Chungbuk 363-883, South Korea [3].

    ,

    1] Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA [2] Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.

    ,

    Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    ,

    FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.

    ,

    Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.

    ,

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    Source

    Nature 515:7526 2014 Nov 13 pg 274-8

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Cell Culture Techniques
    Cell Differentiation
    Drug Evaluation, Preclinical
    Extracellular Space
    Glycogen Synthase Kinase 3
    Humans
    Microtubule-Associated Proteins
    Models, Biological
    Neural Stem Cells
    Neurites
    Phosphorylation
    Presenilin-1
    Protein Aggregation, Pathological
    Reproducibility of Results
    tau Proteins

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25307057

    Citation

    Choi, Se Hoon, et al. "A Three-dimensional Human Neural Cell Culture Model of Alzheimer's Disease." Nature, vol. 515, no. 7526, 2014, pp. 274-8.
    Choi SH, Kim YH, Hebisch M, et al. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014;515(7526):274-8.
    Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D'Avanzo, C., ... Kim, D. Y. (2014). A three-dimensional human neural cell culture model of Alzheimer's disease. Nature, 515(7526), pp. 274-8. doi:10.1038/nature13800.
    Choi SH, et al. A Three-dimensional Human Neural Cell Culture Model of Alzheimer's Disease. Nature. 2014 Nov 13;515(7526):274-8. PubMed PMID: 25307057.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A three-dimensional human neural cell culture model of Alzheimer's disease. AU - Choi,Se Hoon, AU - Kim,Young Hye, AU - Hebisch,Matthias, AU - Sliwinski,Christopher, AU - Lee,Seungkyu, AU - D'Avanzo,Carla, AU - Chen,Hechao, AU - Hooli,Basavaraj, AU - Asselin,Caroline, AU - Muffat,Julien, AU - Klee,Justin B, AU - Zhang,Can, AU - Wainger,Brian J, AU - Peitz,Michael, AU - Kovacs,Dora M, AU - Woolf,Clifford J, AU - Wagner,Steven L, AU - Tanzi,Rudolph E, AU - Kim,Doo Yeon, Y1 - 2014/10/12/ PY - 2014/01/28/received PY - 2014/08/26/accepted PY - 2014/10/14/entrez PY - 2014/10/14/pubmed PY - 2014/12/17/medline SP - 274 EP - 8 JF - Nature JO - Nature VL - 515 IS - 7526 N2 - 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/25307057/A_three_dimensional_human_neural_cell_culture_model_of_Alzheimer's_disease_ L2 - http://dx.doi.org/10.1038/nature13800 DB - PRIME DP - Unbound Medicine ER -