PMID- 25307057 OWN - NLM STAT- MEDLINE DCOM- 20141215 LR - 20220409 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 515 IP - 7526 DP - 2014 Nov 13 TI - A three-dimensional human neural cell culture model of Alzheimer's disease. PG - 274-8 LID - 10.1038/nature13800 [doi] AB - Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-beta plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-beta 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-beta-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-beta species and phosphorylated tau but did not demonstrate amyloid-beta plaques or neurofibrillary tangles. Here we report that FAD mutations in beta-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-beta, including amyloid-beta 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-beta generation with beta- or gamma-secretase inhibitors not only decreased amyloid-beta pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-beta-mediated tau phosphorylation. We have successfully recapitulated amyloid-beta 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. FAU - Choi, Se Hoon AU - Choi SH AD - 1] Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA [2]. FAU - Kim, Young Hye AU - Kim YH AD - 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]. FAU - Hebisch, Matthias AU - Hebisch M AD - 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. FAU - Sliwinski, Christopher AU - Sliwinski C AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Lee, Seungkyu AU - Lee S AD - FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA. FAU - D'Avanzo, Carla AU - D'Avanzo C AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Chen, Hechao AU - Chen H AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Hooli, Basavaraj AU - Hooli B AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Asselin, Caroline AU - Asselin C AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Muffat, Julien AU - Muffat J AD - The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. FAU - Klee, Justin B AU - Klee JB AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Zhang, Can AU - Zhang C AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Wainger, Brian J AU - Wainger BJ AD - FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA. FAU - Peitz, Michael AU - Peitz M AD - Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, 53127 Bonn, Germany. FAU - Kovacs, Dora M AU - Kovacs DM AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Woolf, Clifford J AU - Woolf CJ AD - FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA. FAU - Wagner, Steven L AU - Wagner SL AD - Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA. FAU - Tanzi, Rudolph E AU - Tanzi RE AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Kim, Doo Yeon AU - Kim DY AD - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. LA - eng GR - R01 NS045860/NS/NINDS NIH HHS/United States GR - RF1 AG048080/AG/NIA NIH HHS/United States GR - P01 AG015379/AG/NIA NIH HHS/United States GR - P30 DK043351/DK/NIDDK NIH HHS/United States GR - P30 NS045776/NS/NINDS NIH HHS/United States GR - R01 AG014713/AG/NIA NIH HHS/United States GR - 5R37MH060009/MH/NIMH NIH HHS/United States GR - R21 AG031483/AG/NIA NIH HHS/United States GR - P30 AG062421/AG/NIA NIH HHS/United States GR - 5P01AG15379/AG/NIA NIH HHS/United States GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - P50 AG005134/AG/NIA NIH HHS/United States GR - P01 AG004953/AG/NIA NIH HHS/United States GR - P30 DK057521/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141012 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Amyloid beta-Peptides) RN - 0 (MAP2 protein, human) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Presenilin-1) RN - 0 (presenilin 1, mouse) RN - 0 (tau Proteins) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM CIN - Nat Rev Neurosci. 2014 Dec;15(12):765. PMID: 25354484 CIN - Nat Rev Drug Discov. 2014 Dec;13(12):887. PMID: 25435212 MH - Alzheimer Disease/genetics/*metabolism/*pathology MH - Amyloid beta-Peptides/chemistry/genetics/metabolism MH - Cell Culture Techniques/*methods MH - Cell Differentiation MH - Drug Evaluation, Preclinical/methods MH - Extracellular Space/metabolism MH - Glycogen Synthase Kinase 3/metabolism MH - Humans MH - Microtubule-Associated Proteins/metabolism MH - *Models, Biological MH - Neural Stem Cells/*metabolism/pathology MH - Neurites/metabolism MH - Phosphorylation MH - Presenilin-1/metabolism MH - Protein Aggregation, Pathological MH - Reproducibility of Results MH - tau Proteins/chemistry/metabolism PMC - PMC4366007 MID - NIHMS656312 EDAT- 2014/10/14 06:00 MHDA- 2014/12/17 06:00 PMCR- 2015/05/13 CRDT- 2014/10/14 06:00 PHST- 2014/01/28 00:00 [received] PHST- 2014/08/26 00:00 [accepted] PHST- 2014/10/14 06:00 [entrez] PHST- 2014/10/14 06:00 [pubmed] PHST- 2014/12/17 06:00 [medline] PHST- 2015/05/13 00:00 [pmc-release] AID - nature13800 [pii] AID - 10.1038/nature13800 [doi] PST - ppublish SO - Nature. 2014 Nov 13;515(7526):274-8. doi: 10.1038/nature13800. Epub 2014 Oct 12.