Skip to main content
×
×
Home

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

  • J. P. Robbins (a1) and J. Price (a1)
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.

Copyright
Corresponding author
*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: jacqueline.robbins@kcl.ac.uk)
References
Hide All
Bellin, M, Marchetto, MC, Gage, FH, Mummery, CL (2012). Induced pluripotent stem cells: the new patient? Nature Reviews Molecular Cell Biology 13, 713726.
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, 933945.
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, 274278.
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, 10791088.
Duff, K (2001). Transgenic mouse models of Alzheimer's disease: phenotype and mechanisms of pathogenesis. Biochemical Society Symposium 67, 195202.
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, 33453359.
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, 216220.
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, 30693077.
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, 487496.
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, 22482253.
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, S4S9.
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, 7489.
Meissner, A, Mikkelsen, TS, Gu, H, Wernig, M, Hanna, J (2008). Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766770.
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, 705718.
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, 491498.
Musunuru, K (2013). Genome editing of human pluripotent stem cells to generate human cellular disease models. Disease Models and Mechanisms 6, 896904.
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, 125129.
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, 154163.
Rohani, L, Johnson, AA, Arnold, A, Stolzing, A (2014). The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell 13, 27.
Ross, CA, Akimov, SS (2014). Human-induced pluripotent stem cells: potential for neurodegenerative diseases. Human Molecular Genetics 23, 1726.
Roychaudhuri, R, Yang, M, Hoshi, MM, Teplow, DB (2009) Amyloid β-protein assembly and Alzheimer disease. Journal of Biological Chemistry 284, 47494753.
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, 171179.
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, 413.
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.
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, 124129.
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, 477486.
Takahashi, K, Yamanaka, S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663676.
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, 213227.
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, 45304539.
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.
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, 785798.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 97
Total number of PDF views: 362 *
Loading metrics...

Abstract views

Total abstract views: 1387 *
Loading metrics...

* Views captured on Cambridge Core between 14th August 2017 - 17th August 2018. This data will be updated every 24 hours.