title: 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.
authors.affiliation: 1] Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA [2].
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Choi
authors.affiliation: 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].
authors.forename: Young Hye
authors.initials: YH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebisch
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sliwinski
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Seungkyu
authors.initials: S
authors.lastname: Lee
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: D'Avanzo
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Hechao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Basavaraj
authors.initials: B
authors.lastname: Hooli
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Asselin
authors.affiliation: The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Muffat
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Klee
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wainger
authors.affiliation: Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Peitz
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005110:Extracellular Space / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D016501:Neurites / Q000378:metabolism; D010766:Phosphorylation; D053764:Presenilin-1 / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D015203:Reproducibility of Results; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D053764:Presenilin-1; C580804:presenilin 1, mouse; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3