Induced pluripotent stem cells as a discovery tool for Alzheimer׳s disease
Open accessAbstract
The ability to accurately and systematically evaluate the cellular mechanisms underlying human neurodegenerative disorders such as Alzheimer׳s disease (AD) should lead to advancements in therapeutics. Recent developments in human induced pluripotent stem cells (iPSCs) have afforded the opportunity to use human neurons and glia to study cellular changes involved in neurological diseases. iPSCs have the potential to be differentiated into AD-relevant cell types, including forebrain neurons, astrocytes, and microglia. This permits the evaluation of individual cell types in isolation or in concert, thus modeling the interdependence of cell types within the brain. When discussing the potential of modeling AD with iPSCs, it is important to remember that the umbrella diagnosis of "Alzheimer׳s disease" represents a disease that is heterogeneous in terms of age of onset, underlying causes, and at times precise pathology. The ability of iPSCs to be derived from an array of AD patients allows for a closer examination of the mechanism of disease progression in particular subsets of subjects, who may have different mutations and allelic variants affecting their risk for disease. Disease mechanisms can be probed both by the genetic manipulation of iPSCs and by modifications to the cellular environment by chemical treatment. These studies may lead not only to the refinement of known pathways implicated in AD, but also to the identification of novel pathways heretofore unaffiliated with disease pathology. In this review, we describe the potential of iPSC models to transform our understanding of AD and to lead to valuable advancements in therapeutics. This article is part of a Special Issue entitled SI: Exploiting human neurons.
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Cerebral organoids derived from AD patient-specific iPSCs can recapture patient-specific phenotypes and hence serve as excellent disease models for AD research and drug development.
“Cerebral organoids derived from AD patient-specific iPSCs can recapture patient-specific phenotypes and hence serve as excellent disease models for AD research and drug development [51–53].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [51]
Section 3.2 reports distinct cellular phenotypes in iPSC-derived neurons from different AD patients, and Section 6.2 discusses their potential for drug screening. But Section 6.3 describes cerebral organoids only as a developing approach that recapitulates aspects of cortical development; it does not establish that AD patient-derived organoids recapture patient-specific disease phenotypes or are already excellent AD drug-development models. Page numbers were not available in our copy. (LLM, conf=0.88)
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Cites
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009) · Nature Biotechnology · doi:10.1038/nbt.1529 · Cited by 3,620 · see citing works
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174 · see citing works
Eiraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Matsumura, M., Wataya, T., Nishiyama, A., Muguruma, K., & Sasai, Y. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.09.002 · Cited by 1,522 · see citing works
Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., Hefferan, M. P., Van Gorp, S., Nazor, K. L., Boscolo, F. S., et al. (2012) · Nature · doi:10.1038/nature10821 · Cited by 1,253 · see citing works
A three-dimensional human neural cell culture model of Alzheimer’s disease
Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C., Chen, H., Hooli, B., Asselin, C., Muffat, J., et al. (2014) · Nature · doi:10.1038/nature13800 · Cited by 1,195 · see citing works
Human iPSC-based modeling of late-onset disease via progerin-induced aging
Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777 · see citing works
Kondo, T., Asai, M., Tsukita, K., Kutoku, Y., Ohsawa, Y., Sunada, Y., Imamura, K., Egawa, N., Yahata, N., Okita, K., et al. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.01.009 · Cited by 741 · see citing works
Modeling familial Alzheimer's disease with induced pluripotent stem cells
Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., & Suzuki, N. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr394 · Cited by 599 · see citing works
CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology
Initiative, T. A. D. N., Bradshaw, E. M., Chibnik, L. B., Keenan, B. T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L. L., Imboywa, S., Lee, M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3435 · Cited by 570 · see citing works
Cunningham, M., Cho, J.-H., Leung, A., Savvidis, G., Ahn, S., Moon, M., Lee, P. K. J., Han, J. J., Azimi, N., Kim, K.-S., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.10.006 · Cited by 218 · see citing works
Generation of microglial cells from mouse embryonic stem cells
Beutner, C., Roy, K., Linnartz, B., Napoli, I., & Neumann, H. (2010) · Nature Protocols · doi:10.1038/nprot.2010.90 · Cited by 85 · see citing works
Flagged first, then by citations
Research works printed but not linked: 51
- Bekris LM Yu CE Bird TD Tsuang DW 2010 Genetics of Alzheimer disease J Geriatr Psychiatry Neurol 23 213 227 21045163 PMC3044597
- Brennand K Savas JN Kim Y Tran N Simone A Hashimoto-Torii K Beaumont KG Kim HJ Topol A Ladran I Abdelrahim M Matikainen-Ankney B Chao SH MrSich M Rakic P Fang G Zhang B Yates JR 3rd Gage FH 2015 Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia Mol Psychiatry 3 361 368 24686136 PMC4182344
- Bertram L Lange C Mullin K Parkinson M Hsiao M Hogan MF Schjeide BM Hooli B Divito J Ionita I Jiang H Laird N Moscarillo T Ohlsen KL Elliott K Wang X HuLince D Ryder M Murphy A Wagner SL Blacker D Becker KD Tanzi RE 2008 Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE Am J Hum Genet 83 623 632 18976728 PMC2668052
- Birch AM Katsouri L Sastre M 2014 Modulation of inflammation in transgenic models of Alzheimer's disease J Neuroinflamm 11 25 PMC3922595 24490742
- Bissonnette CJ Lyass L Bhattacharyya BJ Belmadani A Miller RJ Kessler JA 2011 The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells Stem Cells 29 802 811 21381151 PMC3107131
- Boisvert EM Denton K Lei L Li XJ 2013 The specification of telencephalic glutamatergic neurons from human pluripotent stem cells J Vis Exp 74 PMC3656538 23603787
- Caiazzo M Giannelli S Valente P Lignani G Carissimo A Sessa A Colasante G Bartolomeo R Massimino L Ferroni S Settembre C Benfenati F Broccoli V 2015 Direct conversion of fibroblasts into functional astrocytes by defined transcription factors Stem Cell Rep 4 25 36 PMC4297873 25556566
- Campos PB Paulsen BS Rehen SK 2014 Accelerating neuronal aging in in vitro model brain disorders: a focus on reactive oxygen species Front Aging Neurosci 6 292 25386139 PMC4209886
- Cataldo AM Peterhoff CM Troncoso JC Gomez-Isla T Hyman BT Nixon RA 2000 Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations Am J Pathol 157 277 286 10880397 PMC1850219
- Cataldo AM Petanceska S Terio NB Peterhoff CM Durham R Mercken M Mehta PD Buxbaum J Haroutunian V Nixon RA 2004 Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome Neurobiol Aging 25 1263 1272 15465622
- Duan L Bhattacharyya BJ Belmadani A Pan L Miller RJ Kessler JA 2014 Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death Mol Neurodegener 9 3 24401693 PMC3896712
- Emdad L D'Souza SL Kothari HP Qadeer ZA Germano IM 2012 Efficient differentiation of human embryonic and induced pluripotent stem cells into functional astrocytes Stem Cells Dev 21 404 410 21631388
- Franco R Cedazo-Minguez A 2014 Successful therapies for Alzheimer's disease: why so many in animal models and none in humans? Front Pharmacol 5 146 25009496 PMC4070393
- Griciuc A Serrano-Pozo A Parrado AR Lesinski AN Asselin CN Mullin K Hooli B Choi SH Hyman BT Tanzi RE 2013 Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta Neuron 78 631 643 23623698 PMC3706457
- Guerreiro R Wojtas A Bras J Carrasquillo M Rogaeva E Majounie E Cruchaga C Sassi C Kauwe JS Younkin S Hazrati L Collinge J Pocock J Lashley T Williams J Lambert JC Amouyel P Goate A Rademakers R Morgan K Powell J St George-Hyslop P Singleton A Hardy J 2013 TREM2 variants in Alzheimer's disease N Engl J Med 368 117 127 23150934 PMC3631573
- Hardy J Selkoe DJ 2002 The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics Science 297 353 356 12130773
- Hollingworth P Sweet R Sims R Harold D Russo G Abraham R Stretton A Jones N Gerrish A Chapman J Ivanov D Moskvina V Lovestone S Priotsi P Lupton M Brayne C Gill M Lawlor B Lynch A Craig D McGuinness B Johnston J Holmes C Livingston G Bass NJ Gurling H McQuillin A Holmans P Jones L Devlin B Klei L Barmada MM Demirci FY DeKosky ST Lopez OL Passmore P Owen MJ O'Donovan MC Mayeux R Kamboh MI Williams J 2012 Genome-wide association study of Alzheimer's disease with psychotic symptoms Mol Psychiatry 17 1316 1327 22005930 PMC3272435
- Jiang T Yu JT Zhu XC Tan L 2013 TREM2 in Alzheimer's disease Mol Neurobiol 48 180 185 23407992
- Koch P Tamboli IY Mertens J Wunderlich P Ladewig J Stuber K Esselmann H Wiltfang J Brustle O Walter J 2012 Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of gamma-secretase activity in endogenous amyloid-beta generation Am J Pathol 180 2404 2416 22510327
- Krencik R Zhang SC 2011 Directed differentiation of functional astroglial subtypes from human pluripotent stem cells Nat Protoc 6 1710 1717 22011653 PMC3198813
- Lancaster MA Renner M Martin CA Wenzel D Bicknell LS Hurles ME Homfray T Penninger JM Jackson AP Knoblich JA 2013 Cerebral organoids model human brain development and microcephaly Nature 501 373 379 23995685 PMC3817409
- Li HL Nakano T Hotta A 2014 Genetic correction using engineered nucleases for gene therapy applications Dev Growth Differ 56 63 77 24329887
- Liu Q Waltz S Woodruff G Ouyang J Israel MA Herrera C Sarsoza F Tanzi RE Koo EH Ringman JM Goldstein LS Wagner SL Yuan SH 2014 Effect of potent gamma-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers JAMA Neurol 71 1481 1489 25285942 PMC4374637
- Mahairaki V Ryu J Peters A Chang Q Li T Park TS Burridge PW Talbot CC Jr Asnaghi L Martin LJ Zambidis ET Koliatsos VE 2014 Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties Stem Cells Dev 23 2996 3010 25027006 PMC4267410
- Moore S Evans LD Andersson T Portelius E Smith J Dias TB Saurat N McGlade A Kirwan P Blennow K Hardy J Zetterberg H Livesey FJ 2015 APP metabolism regulates tau proteostasis in human cerebral cortex neurons Cell Rep 11 689 696 25921538 PMC4431668
- Mosher KI Wyss-Coray T 2014 Microglial dysfunction in brain aging and Alzheimer's disease Biochem Pharmacol 88 594 604 24445162 PMC3972294
- Muratore CR Rice HC Srikanth P Callahan DG Shin T Benjamin LN Walsh DM Selkoe DJ Young-Pearse TL 2014 The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons Hum Mol Genet 23 3523 3536 24524897 PMC4049307
- Nicholas CR Chen J Tang Y Southwell DG Chalmers N Vogt D Arnold CM Chen YJ Stanley EG Elefanty AG Sasai Y Alvarez-Buylla A Rubenstein JL Kriegstein AR 2013 Functional maturation of hPSC-derived forebrain inter-neurons requires an extended timeline and mimics human neural development Cell Stem Cell 12 573 586 23642366 PMC3699205
- Nilsberth C Westlind-Danielsson A Eckman CB Condron MM Axelman K Forsell C Stenh C Luthman J Teplow DB Younkin SG Naslund J Lannfelt L 2001 The ‘Arctic’ APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation Nat Neurosci 4 887 893 11528419
- Ransohoff RM Cardona AE 2010 The myeloid cells of the central nervous system parenchyma Nature 468 253 262 21068834
- Rice HC Young-Pearse TL Selkoe DJ 2013 Systematic evaluation of candidate ligands regulating ectodomain shedding of amyloid precursor protein Biochemistry 52 3264 3277 23597280 PMC3809327
- Schellenberg GD Montine TJ 2012 The genetics and neuropathology of Alzheimer's disease Acta Neuropathol 124 305 323 22618995 PMC3708460
- Selkoe DJ 2001 Alzheimer's disease: genes, proteins, and therapy Physiol Rev 81 741 766 11274343
- Shi Y Kirwan P Smith J MacLean G Orkin SH Livesey FJ 2012 A human stem cell model of early Alzheimer's disease pathology in Down syndrome Sci Transl Med 4 124ra29 PMC4129935 22344463
- Soldner F Jaenisch R 2012 Medicine: iPSC disease modeling Science 338 1155 1156 23197518
- Spillantini MG Goedert M 2013 Tau pathology and neurodegeneration Lancet Neurol 12 609 622 23684085
- Sproul AA Jacob S Pre D Kim SH Nestor MW Navarro-Sobrino M Santa-Maria I Zimmer M Aubry S Steele JW Kahler DJ Dranovsky A Arancio O Crary JF Gandy S Noggle SA 2014 Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors PLoS One 9 e84547 24416243 PMC3885572
- Takahashi K Tanabe K Ohnuki M Narita M Ichisaka T Tomoda K Yamanaka S 2007 Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 131 861 872 18035408
- Thies W Bleiler L 2013 2013 Alzheimer's disease facts and figures Alzheimers Dement 9 208 245 23507120
- Vazin T Ball KA Lu H Park H Ataeijannati Y Head-Gordon T Poo MM Schaffer DV 2014 Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease Neurobiol Dis 62 62 72 24055772 PMC4122237
- Wicklund L Leao RN Stromberg AM Mousavi M Hovatta O Nordberg A Marutle A 2010 Beta-amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic neurons PLoS One 5 e15600 21179413 PMC3003688
- Wojda U Kuznicki J 2013 Alzheimer's disease modeling: ups, downs, and perspectives for human induced pluripotent stem cells J Alzheimers Dis 34 563 588 23313930
- Wolfe MS 2010 Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases Biol Chem 391 839 847 20482315 PMC2997569
- Woodruff G Young JE Martinez FJ Buen F Gore A Kinaga J Li Z Yuan SH Zhang K Goldstein LS 2013 The presenilin-1 DeltaE9 mutation results in reduced gamma-secretase activity, but not total loss of PS1 function, in isogenic human stem cells Cell Rep 5 974 985 24239350 PMC3867011
- 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 Res 10 213 227 23305945
- 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-Abeta drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease PLoS One 6 e25788 21984949 PMC3184175
- Yan Y Shin S Jha BS Liu Q Sheng J Li F Zhan M Davis J Bharti K Zeng X Rao M Malik N Vemuri MC 2013 Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells Stem Cells Transl Med 2 862 870 24113065 PMC3808201
- Young JE Boulanger-Weill J Williams DA Woodruff G Buen F Revilla AC Herrera C Israel MA Yuan SH Edland SD Goldstein LS 2015 Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells Cell Stem Cell 16 373 385 25772071 PMC4388804
- Yuan SH Martin J Elia J Flippin J Paramban RI Hefferan MP Vidal JG Mu Y Killian RL Israel MA Emre N Marsala S Marsala M Gage FH Goldstein LS Carson CT 2011 Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells PLoS One 6 e17540 21407814 PMC3047583
- Zeng H Guo M Martins-Taylor K Wang X Zhang Z Park JW Zhan S Kronenberg MS Lichtler A Liu HX Chen FP Yue L Li XJ Xu RH 2010 Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells PLoS One 5 e11853 20686615 PMC2912324
- Zhang Y Pak C 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 23764284 PMC3751803
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APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793 · see citing works
Sullivan, S. E., Liao, M., Smith, R. V., White, C., Lagomarsino, V. N., Xu, J., Taga, M., Bennett, D. A., De Jager, P. L., & Young-Pearse, T. L. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddy376 · Cited by 44 · see citing works
Self-citationLu, W., Kawatani, K., Ren, Y., Nambara, T., Jia, L., Jeevaratnam, S., Lee, E., Martinez, P. R., Izhar, T., Wang, N., et al. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-01982-0 · Cited by 4 · see citing works
- Authors
- Sullivan, S. E., & Young-Pearse, T. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 1656
- Pages
- 98-106
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC4833689
- OpenAlex
- W1933614530
- Cited by
- 50
- References
- 11
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 3 · 2022: 6 · 2021: 7 · 2020: 4 · 2019: 9 · 2018: 4 · 2017: 5 · 2016: 6
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Health (U01 AG046152, R01 MH101148, R33 AG049864)
- Harvard NeuroDiscovery Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- induced pluripotent stem cells, Alzheimer's disease, iPSC-derived neurons, astrocytes, microglia, disease modeling, neurodegeneration, disease heterogeneity, therapeutic discovery
- MeSH terms
- Alzheimer Disease, Animals, Humans, Induced Pluripotent Stem Cells
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