title: 3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish".
abstract: Alzheimer's disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 02129, Charlestown, MA, USA.
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Cheongju-si, Chungbuk, 363-883, Republic of Korea.
authors.forename: Young Hye
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 02129, Charlestown, MA, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 02129, Charlestown, MA, USA. tanzi@helix.mgh.harvard.edu.
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, 02129, Charlestown, MA, USA. dkim@helix.mgh.harvard.edu.
authors.forename: Doo Yeon
authors.identifier: 0000-0002-6969-0340
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease; D018929:Cell Culture Techniques; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology*
keywords: Alzheimer’s disease; Amyloid plaques; High-throughput drug screening; Induced-pluripotent stem cell; Neurofibrillary tangles; Three-dimensional culture