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Human induced pluripotent stem cells as a research tool in Alzheimer's disease

Published online by Cambridge University Press:  14 August 2017

J. P. Robbins  and
J. Price
J. P. Robbins*
Affiliation:
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
J. Price
Affiliation:
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
*
*Address for correspondence: J. P. Robbins, Department of Basic and Cellular Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. (Email: [email protected])
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Abstract

Human-induced pluripotent stem cells (iPSCs) offer a novel, timely approach for investigating the aetiology of neuropsychiatric disorders. Although we are starting to gain more insight into the specific mechanisms that cause Alzheimer's disease and other forms of dementia, this has not resulted in therapies to slow the pathological processes. Animal models have been paramount in studying the neurobiological processes underlying psychiatric disorders. Nonetheless, these human conditions cannot be entirely recapitulated in rodents. Human cell models derived from patients’ cells now offer new hope for improving our understanding of the early molecular stages of these diseases, through to validating therapeutics. The impact of dementia is increasing, and a new model to investigate the early stages of this disease is heralded as an essential, new platform for translational research. In this paper, we review current literature using iPSCs to study Alzheimer's disease, describe drug discovery efforts using this platform, and discuss the future potential for this technology in psychiatry research.

Keywords

Alzheimer's diseasecell modelsdementiadisease modellinginduced pluripotent stem cells
Type
Short Teaching Article
Information
Psychological Medicine , Volume 47 , Issue 15 , November 2017 , pp. 2587 - 2592
Copyright
Copyright © Cambridge University Press 2017 

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References

Bellin, M, Marchetto, MC, Gage, FH, Mummery, CL (2012). Induced pluripotent stem cells: the new patient? Nature Reviews Molecular Cell Biology 13, 713–726.CrossRefGoogle ScholarPubMed
Brennand, K, Marchetto, M, Benvenisty, N, Brüstle, O, Ebert, A, Izpisua Belmonte, J, Kaykas, A, Lancaster, M, Livesey, F, McConnell, M, McKay, R, Morrow, E, Muotri, A, Panchision, D, Rubin, L, Sawa, A, Soldner, F, Song, H, Studer, L, Temple, S, Vaccarino, F, Wu, J, Vanderhaeghen, P, Gage, F, Jaenisch, R (2015). Creating patient-specific neural cells for the in vitro study of brain disorders. Stem Cell Reports 5, 933–945.CrossRefGoogle ScholarPubMed
Choi, SH, Kim, YH, Hebisch, M, Sliwinski, C, Lee, S, D'Avanzo, C, Chen, H, Hooli, B, Asselin, C, Muffat, J, Klee, JB, Zhang, C, Wainger, BJ, Peitz, M, Kovacs, DM, Woolf, CJ, Wagner, SL, Tanzi, RE, Kim, DY (2014). A three-dimensional human neural cell culture model of Alzheimer/’s disease. Nature 515, 274–278.CrossRefGoogle ScholarPubMed
Cocks, G, Curran, S, Gami, P, Uwanogho, D, Jeffries, AR, Kathuria, A, Lucchesi, W, Wood, V, Dixon, R, Ogilvie, C, Steckler, T, Price, J (2014). The utility of patient specific induced pluripotent stem cells for the modelling of autistic spectrum disorders. Psychopharmacology 231, 1079–1088.CrossRefGoogle ScholarPubMed
Duff, K (2001). Transgenic mouse models of Alzheimer's disease: phenotype and mechanisms of pathogenesis. Biochemical Society Symposium 67, 195–202.Google Scholar
Iovino, M, Agathou, S, Gonzalez-Rueda, A, Del Castillo Velasco-Herrera, M, Borroni, B, Alberici, A, Lynch, T, O'Dowd, S, Geti, I, Gaffney, D, Vallier, L, Paulsen, O, Karadottir, RT, Spillantini, MG (2015). Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain 138, 3345–3359.CrossRefGoogle ScholarPubMed
Israel, MA, Yuan, SH, Bardy, C, Reyna, SM, Mu, Y, Herrera, C, Hefferan, MP, Van Gorp, S, Nazor, KL, Boscolo, FS, Carson, CT, Laurent, LC, Marsala, M, Gage, FH, Remes, AM, Koo, EH, Goldstein, LSB (2012). Probing sporadic and familial Alzheimer/’s disease using induced pluripotent stem cells. Nature 482, 216–220.CrossRefGoogle ScholarPubMed
Johnson, MA, Weick, JP, Pearce, RA, Zhang, SC (2007). Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. Journal of Neuroscience 27, 3069–3077.CrossRefGoogle ScholarPubMed
Kondo, T, Asai, M, Tsukita, K, Kutoku, Y, Ohsawa, Y, Sunada, Y, Imamura, K, Egawa, N, Yahata, N, Okita, K, Takahashi, K, Asaka, I, Aoi, T, Watanabe, A, Watanabe, K, Kadoya, C, Nakano, R, Watanabe, D, Maruyama, K, Hori, O, Hibino, S, Choshi, T, Nakahata, T, Hioki, H, Kaneko, T, Naitoh, M, Yoshikawa, K, Yamawaki, S, Suzuki, S, Hata, R, Ueno, S, Seki, T, Kobayashi, K, Toda, T, Murakami, K, Irie, K, Klein, WL, Mori, H, Asada, T, Takahashi, R, Iwata, N, Yamanaka, S, Inoue, H (2013). Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12, 487–496.CrossRefGoogle ScholarPubMed
Lapasset, L, Milhavet, O, Prieur, A, Besnard, E, Babled, A, Ait-Hamou, N, Leschik, J, Pellestor, F, Ramirez, JM, De Vos, J, Lehmann, S, Lemaitre, JM (2011). Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & Development 25, 2248–2253.CrossRefGoogle ScholarPubMed
Lobo, A, Launer, LJ, Fratiglioni, L, Andersen, K, Di Carlo, A, Breteler, MM, Copeland, JR, Dartigues, JF, Jagger, C, Martinez-Lage, J, Soininen, H, Hofman, A (2000). Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology 54, S4–S9.Google ScholarPubMed
Markou, A, Chiamulera, C, Geyer, MA, Tricklebank, M, Steckler, T (2009). Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology 34, 74–89.CrossRefGoogle ScholarPubMed
Meissner, A, Mikkelsen, TS, Gu, H, Wernig, M, Hanna, J (2008). Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770.CrossRefGoogle ScholarPubMed
Mertens, J, Paquola Apuã, CM, Ku, M, Hatch, E, Böhnke, L, Ladjevardi, S, McGrath, S, Campbell, B, Lee, H, Herdy Joseph, R, Gonçalves, JT, Toda, T, Kim, Y, Winkler, J, Yao, J, Hetzer, MW, Gage, FH (2015). Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17, 705–718.CrossRefGoogle ScholarPubMed
Mertens, J, Stüber, K, Wunderlich, P, Ladewig, J, Kesavan Jaideep, C, Vandenberghe, R, Vandenbulcke, M, van Damme, P, Walter, J, Brüstle, O, Koch, P (2013). APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation. Stem Cell Reports 1, 491–498.CrossRefGoogle ScholarPubMed
Musunuru, K (2013). Genome editing of human pluripotent stem cells to generate human cellular disease models. Disease Models and Mechanisms 6, 896–904.Google ScholarPubMed
Paquet, D, Kwart, D, Chen, A, Sproul, A, Jacob, S, Teo, S, Olsen, KM, Gregg, A, Noggle, S, Tessier-Lavigne, M (2016). Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature 533, 125–129.CrossRefGoogle ScholarPubMed
Qi, Y, Zhang, X, Renier, N, Wu, Z, Atkin, T, Sun, Z, Ozair, MZ, Tchieu, J, Zimmer, B, Fattahi, F, Ganat, Y, Azevedo, R, Zeltner, N, Brivanlou, AH, Karayiorgou, M, Gogos, J, Tomishima, M, Tessier-Lavigne, M, Shi, S, Studer, L (2017). Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells. Nature Biotechnology 35, 154–163.CrossRefGoogle ScholarPubMed
Rohani, L, Johnson, AA, Arnold, A, Stolzing, A (2014). The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell 13, 2–7.CrossRefGoogle ScholarPubMed
Ross, CA, Akimov, SS (2014). Human-induced pluripotent stem cells: potential for neurodegenerative diseases. Human Molecular Genetics 23, 17–26.CrossRefGoogle ScholarPubMed
Roychaudhuri, R, Yang, M, Hoshi, MM, Teplow, DB (2009) Amyloid β-protein assembly and Alzheimer disease. Journal of Biological Chemistry 284, 4749–4753.CrossRefGoogle ScholarPubMed
Ryan, DA, Narrow, WC, Federoff, HJ, Bowers, WJ (2010). An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studies. Journal of Neuroscience Methods 190, 171–179.CrossRefGoogle ScholarPubMed
Santostefano, KE, Hamazaki, T, Biel, NM, Jin, S, Umezawa, A, Terada, N (2015) A practical guide to induced pluripotent stem cell research using patient samples. Laboratory Investigation 95, 4–13.CrossRefGoogle ScholarPubMed
Saraceno, C, Musardo, S, Marcello, E, Pelucchi, S, Di Luca, M (2013). Modeling Alzheimer's disease: from past to future. Frontiers in Pharmacology 4, 77.CrossRefGoogle ScholarPubMed
Shi, Y, Kirwan, P, Smith, J, MacLean, G, Orkin, SH, Livesey, FJ (2012 a). A human stem cell model of early Alzheimer's disease pathology in down syndrome. Science Translational Medicine 4, 124–129.CrossRefGoogle ScholarPubMed
Shi, Y, Kirwan, P, Smith, J, Robinson, HPC, Livesey, FJ (2012 b). Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neuroscience 15, 477–486.CrossRefGoogle ScholarPubMed
Takahashi, K, Yamanaka, S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676.CrossRefGoogle ScholarPubMed
Xu, X, Lei, Y, Luo, J, Wang, J, Zhang, S, Yang, XJ, Sun, M, Nuwaysir, E, Fan, G, Zhao, J, Lei, L, Zhong, Z (2013). Prevention of beta-amyloid induced toxicity in human iPS cell-derived neurons by inhibition of cyclin-dependent kinases and associated cell cycle events. Stem Cell Research 10, 213–227.CrossRefGoogle ScholarPubMed
Yagi, T, Ito, D, Okada, Y, Akamatsu, W, Nihei, Y, Yoshizaki, T, Yamanaka, S, Okano, H, Suzuki, N (2011). Modeling familial Alzheimer's disease with induced pluripotent stem cells. Human Molecular Genetics 20, 4530–4539.CrossRefGoogle ScholarPubMed
Yahata, N, Asai, M, Kitaoka, S, Takahashi, K, Asaka, I, Hioki, H, Kaneko, T, Maruyama, K, Saido, TC, Nakahata, T, Asada, T, Yamanaka, S, Iwata, N, Inoue, H (2011). Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. PLoS ONE 6, e25788.CrossRefGoogle ScholarPubMed
Zhang, Y, Pak, CH, Han, Y, Ahlenius, H, Zhang, Z, Chanda, S, Marro, S, Patzke, C, Acuna, C, Covy, J, Xu, W, Yang, N, Danko, T, Chen, L, Wernig, M, Sudhof, TC (2013). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785–798.CrossRefGoogle ScholarPubMed