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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2017

Open Access 01-12-2017 | Review

Stem cell models of Alzheimer’s disease: progress and challenges

Published in: Alzheimer's Research & Therapy | Issue 1/2017

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Abstract

A major challenge to our understanding of the molecular mechanisms of Alzheimer’s disease (AD) has been the lack of physiologically relevant in vitro models which capture the precise patient genome, in the cell type of interest, with physiological expression levels of the gene(s) of interest. Induced pluripotent stem cell (iPSC) technology, together with advances in 2D and 3D neuronal differentiation, offers a unique opportunity to overcome this challenge and generate a limitless supply of human neurons for in vitro studies. iPSC-neuron models have been widely employed to model AD and we discuss in this review the progress that has been made to date using patient-derived neurons to recapitulate key aspects of AD pathology and how these models have contributed to a deeper understanding of AD molecular mechanisms, as well as addressing the key challenges posed by using this technology and what progress is being made to overcome these. Finally, we highlight future directions for the use of iPSC-neurons in AD research and highlight the potential value of this technology to neurodegenerative research in the coming years.
Literature
1.
2.
Morrissette DA, Parachikova A, Green KN, LaFerla FM. Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem. 2009;284:6033–7.PubMedCrossRef
3.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.PubMedCrossRef
4.
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.PubMedCrossRef
5.
6.
7.
Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999;66:137–47.PubMedPubMedCentralCrossRef
8.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.PubMedCrossRef
9.
10.
Zhang S-C, Wernig M, Duncan ID, Brüstle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 2001;19:1129–33.PubMedCrossRef
11.
Ying Q-L, Stavridis M, Griffiths D, Li M, Smith A. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol. 2003;21:183–6.PubMedCrossRef
12.
Tao Y, Zhang S-C. Neural subtype specification from human pluripotent stem cells. Cell Stem Cell. 2016;19:573–86.PubMedCrossRef
13.
Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275–80.PubMedPubMedCentralCrossRef
14.
Morizane A, Doi D, Kikuchi T, Nishimura K, Takahashi J. Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells. J Neurosci Res. 2011;89:117–26.PubMedCrossRef
15.
Li X-J, Zhang X, Johnson MA, Wang Z-B, Lavaute T, Zhang S-C. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 2009;136:4055–63.PubMedPubMedCentralCrossRef
16.
van de Leemput J, Boles NC, Kiehl TR, Corneo B, Lederman P, Menon V, et al. CORTECON: a temporal transcriptome analysis of in vitro human cerebral cortex development from human embryonic stem cells. Neuron. 2014;83:51–68.PubMedCrossRef
17.
Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008;455:351–7.PubMedCrossRef
18.
Shi Y, Kirwan P, Smith J, Robinson HPC, Livesey FJ. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci. 2012;15:477–86. S1.PubMedCrossRef
19.
Zhang Y, Pak C, Han Y, Ahlenius H, Zhang Z, Chanda S, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron. 2013;78:785–98.PubMedPubMedCentralCrossRef
20.
Qi Y, Zhang X-J, Renier N, Wu Z, Atkin T, Sun Z, et al. Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells. Nat Biotechnol. 2017;35(2):154–63.PubMedCrossRef
21.
Cambray S, Arber C, Little G, Dougalis AG, de Paola V, Ungless MA, et al. Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors. Nat Commun. 2012;3:841.PubMedCrossRef
22.
Maroof AM, Keros S, Tyson JA, Ying S-W, Ganat YM, Merkle FT, et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell. 2013;12:559–72.PubMedPubMedCentralCrossRef
23.
Bissonnette CJ, Lyass L, Bhattacharyya BJ, Belmadani A, Miller RJ, Kessler JA. The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells. 2011;29:802–11.PubMedPubMedCentralCrossRef
24.
Sanalkumar R, Vidyanand S, Lalitha Indulekha C, James J. Neuronal vs. Glial fate of embryonic stem cell-derived neural progenitors (ES-NPs) is determined by FGF2/EGF during proliferation. J Mol Neurosci. 2010;42:17–27.PubMedCrossRef
25.
Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A. 2013;110:4697–702.PubMedPubMedCentralCrossRef
26.
Patani R, Lewis PA, Trabzuni D, Puddifoot CA, Wyllie DJA, Walker R, et al. Investigating the utility of human embryonic stem cell-derived neurons to model ageing and neurodegenerative disease using whole-genome gene expression and splicing analysis. J Neurochem. 2012;122:738–51.PubMedPubMedCentralCrossRef
27.
Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Bräuninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A. 2015;112:15672–7.PubMedPubMedCentralCrossRef
28.
Bosi S, Rauti R, Laishram J, Turco A, Lonardoni D, Nieus T, et al. From 2D to 3D: novel nanostructured scaffolds to investigate signalling in reconstructed neuronal networks. Sci Rep. 2015;5:1–11.CrossRef
29.
Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19:485–502.PubMedPubMedCentralCrossRef
30.
Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–9.PubMedCrossRef
31.
Hejazian LB, Esmaeilzade B, Ghoroghi FM, Hejazian MB, Aslani A, Bakhtiari M. The role of biodegradable engineered nanofiber scaffolds seeded with hair follicle stem cells for tissue engineering. Iran Biomed J. 2012;16:193–201.PubMedPubMedCentral
32.
33.
Uemura M, Refaat MM, Shinoyama M, Hayashi H, Hashimoto N, Takahashi J. Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell-derived neural precursor cells. J Neurosci Res. 2010;88:542–51.PubMed
34.
Edmondson R, Adcock AF, Yang L, Liu G, Diot A, Xirodimas D. Influence of matrices on 3D-cultured prostate cancer cells’ drug response and expression of drug-action associated proteins. PLoS One. 2016;11:e0158116.PubMedPubMedCentralCrossRef
35.
Watanabe K, Kamiya D, Nishiyama A, Katayama T, Nozaki S, Kawasaki H, et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci. 2005;8:288–96.PubMedCrossRef
36.
Smith JR, Vallier L, Lupo G, Alexander M, Harris WA, Pedersen RA. Inhibition of Activin/Nodal signaling promotes specification of human embryonic stem cells into neuroectoderm. Dev Biol. 2008;313:107–17.PubMedCrossRef
37.
Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016;165:1238–54.PubMedPubMedCentralCrossRef
38.
Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. 2016;323:170–82.PubMedCrossRef
39.
Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell. 2008;3:519–32.PubMedCrossRef
40.
Muguruma K, Nishiyama A, Kawakami H, Hashimoto K, Sasai Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 2015;10:537–50.PubMedCrossRef
41.
Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran H-D, Göke J, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell. 2016;19:248–57.PubMedCrossRef
42.
Quadrato G, Brown J, Arlotta P. The promises and challenges of human brain organoids as models of neuropsychiatric disease. Nat Med. 2016;22:1220–8.PubMedCrossRef
43.
44.
Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10:771–85.PubMedCrossRef
45.
Tieng V, Stoppini L, Villy S, Fathi M, Dubois-Dauphin M, Krause K-H. Engineering of midbrain organoids containing long-lived dopaminergic neurons. Stem Cells Dev. 2014;23(13):1535–47.PubMedCrossRef
46.
Paşca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015;12:671–8.PubMedPubMedCentralCrossRef
47.
48.
Li Y, Muffat J, Omer A, Bosch I, Lancaster MA, Sur M, et al. Induction of expansion and folding in human cerebral organoids. Cell Stem Cell. 2017;20(3):385–96.e3.
49.
Bershteyn M, Nowakowski TJ, Pollen AA, Di Lullo E, Nene A, Wynshaw-Boris A, et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell. 2017;20(4):435–49.e4.
50.
Sannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar AK, et al. Restricted location of PSEN2/γ-secretase determines substrate specificity and generates an intracellular Aβ pool. Cell. 2016;166:193–208.PubMedCrossRef
51.
52.
Freude KK, Penjwini M, Davis JL, LaFerla FM, Blurton-Jones M. Soluble Amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. J Biol Chem. 2011;286:24264–74.PubMedPubMedCentralCrossRef
53.
Porayette P, Gallego MJ, Kaltcheva MM, Bowen RL, Vadakkadath Meethal S, Atwood CS. Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells. J Biol Chem. 2009;284:23806–17.PubMedPubMedCentralCrossRef
54.
Yang J, Zhao H, Ma Y, Shi G, Song J, Tang Y, et al. Early pathogenic event of Alzheimer’s disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget. 2017;8(5):7900–913.
55.
Liao M-C, Muratore CR, Gierahn TM, Sullivan SE, Srikanth P, De Jager PL, et al. Single-cell detection of secreted Aβ and sAPPα from human iPSC-derived neurons and astrocytes. J Neurosci. 2016;36:1730–46.PubMedPubMedCentralCrossRef
56.
Brownjohn PW, Smith J, Portelius E, Serneels L, Kvartsberg H, De Strooper B, et al. Phenotypic screening identifies modulators of amyloid precursor protein processing in human stem cell models of Alzheimer’s disease. Stem Cell Rep. 2017;8:870–82.CrossRef
57.
Takamatsu K, Ikeda T, Haruta M, Matsumura K, Ogi Y, Nakagata N, et al. Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2. Stem Cell Res. 2014;13:442–53.PubMedCrossRef
58.
Vazin T, Ball KA, Lu H, Park H, Ataeijannati Y, Head-Gordon T, et al. Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer’s disease. Neurobiol Dis. 2014;62:62–72.PubMedCrossRef
59.
Nieweg K, Andreyeva A, van Stegen B, Tanriöver G, Gottmann K. Alzheimer’s disease-related amyloid-β induces synaptotoxicity in human iPS cell-derived neurons. Cell Death Dis. 2015;6:e1709.PubMedPubMedCentralCrossRef
60.
Sengupta P, Garai K, Sahoo B, Shi Y, Callaway DJE, Maiti S. The amyloid beta peptide (Abeta 1-40) is thermodynamically soluble at physiological concentrations. Biochemistry. 2003;42:10506–13.PubMedCrossRef
61.
Kuo Y-M, Emmerling MR, Lampert HC, Hempelman SR, Kokjohn TA, Woods AS, et al. High levels of circulating Aβ42 are sequestered by plasma proteins in Alzheimer’s disease. Biochem Biophys Res Commun. 1999;257:787–91.PubMedCrossRef
62.
Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, et al. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet. 2011;20:4530–9.PubMedCrossRef
63.
Yahata N, Asai M, Kitaoka S, Takahashi K, Asaka I, Hioki H. Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer’s disease. PLoS One. 2011;6:e25788.PubMedPubMedCentralCrossRef
64.
Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature. 2012;482:216–20.PubMedPubMedCentral
65.
Shi Y, Kirwan P, Smith J, MacLean G, Orkin SH, Livesey FJ. A human stem cell model of early Alzheimer’s disease pathology in Down syndrome. Sci Transl Med. 2012;4:124ra29.PubMedPubMedCentral
66.
Koch P, Tamboli IYIY, Mertens J, Wunderlich P, Ladewig J, Stüber K, et al. Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. Am J Pathol. 2012;180:2404–16.PubMedCrossRef
67.
Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell. 2013;12:487–96.PubMedCrossRef
68.
Duan L, Bhattacharyya BJ, Belmadani A, Pan L, Miller RJ, Kessler JA. Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death. Mol Neurodegener. 2014;9:3.PubMedPubMedCentralCrossRef
69.
Mahairaki V, Ryu J, Peters A, Chang Q, Li T, Park TS, et al. Induced pluripotent stem cells from familial Alzheimer’s disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev. 2014;23:2996–3010.PubMedPubMedCentralCrossRef
70.
Maloney JA, Bainbridge T, Gustafson A, Zhang S, Kyauk R, Steiner P, et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem. 2014;289:30990–1000.PubMedPubMedCentralCrossRef
71.
Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LNP, et al. The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014;23:3523–36.PubMedPubMedCentralCrossRef
72.
Sproul AA, Jacob S, Pre D, Kim SH, Nestor MW, Navarro-Sobrino M, et al. Characterization and molecular profiling of PSEN1 familial Alzheimer’s disease iPSC-derived neural progenitors. PLoS One. 2014;9:e84547.PubMedPubMedCentralCrossRef
73.
Dashinimaev EB, Artyuhov AS, Bolshakov AP, Vorotelyak EA, Vasiliev AV. Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer’s Disease Type Pathology in vitro. J Alzheimer's Dis. 2017;56(2):835–47. doi:10.​3233/​JAD-160945.
74.
Chang C-Y, Chen S-M, Lu H-E, Lai S-M, Lai P-S, Shen P-W, et al. N-butylidenephthalide attenuates Alzheimer’s disease-like cytopathy in Down syndrome induced pluripotent stem cell-derived neurons. Sci Rep. 2015;5:8744.PubMedPubMedCentralCrossRef
75.
Moore S, Evans LDB, Andersson T, Portelius E, Smith J, Dias TB, et al. APP Metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015;11:689–96.PubMedPubMedCentralCrossRef
76.
Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, et al. The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep. 2013;5:974–85.PubMedCrossRef
77.
Bergström P, Agholme L, Nazir FH, Satir TM, Toombs J, Wellington H, et al. Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation. Sci Rep. 2016;6:29200.PubMedPubMedCentralCrossRef
78.
Raja WK, Mungenast AE, Lin Y-T, Ko T, Abdurrob F, Seo J, et al. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS One. 2016;11(9):e0161969.PubMedPubMedCentralCrossRef
79.
Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515:274–8.PubMedPubMedCentralCrossRef
80.
Lee G, Ramirez CN, Kim H, Zeltner N, Liu B, Radu C, et al. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat Biotechnol. 2012;30:1244–8.PubMedPubMedCentralCrossRef
81.
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature Nature. 2012;488:96–9.PubMedCrossRef
82.
Leem JY, Vijayan S, Han P, Cai D, Machura M, Lopes KO, et al. Presenilin 1 is required for maturation and cell surface accumulation of Nicastrin. J Biol Chem. 2002;277:19236–40.PubMedCrossRef
83.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3.PubMedCrossRef
84.
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41:1088–93.PubMedPubMedCentralCrossRef
85.
Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45:1452–8.PubMedPubMedCentralCrossRef
86.
Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832.PubMedPubMedCentralCrossRef
87.
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43:429–35.PubMedPubMedCentralCrossRef
88.
Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43:436–41.PubMedPubMedCentralCrossRef
89.
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 Variants in Alzheimer’s disease. N Engl J Med. 2013;368:117–27.PubMedCrossRef
90.
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368:107–16.PubMedCrossRef
91.
Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, et al. Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell. 2015;16:373–85.PubMedPubMedCentralCrossRef
92.
Huang Y-WA, Zhou B, Wernig M, Südhof TC. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell. 2017;168(3):427–41.e21.
93.
Schröter F, Sleegers K, Van Cauwenberghe C, Bohndorf M, Wruck W, Van Broeckhoven C, et al. Lymphoblast-derived integration-free iPSC lines from a female and male Alzheimer’s disease patient expressing different copy numbers of a coding CNV in the Alzheimer risk gene CR1. Stem Cell Res. 2016;17:560–3.PubMedCrossRef
94.
Mufson EJ, Ma SY, Dills J, Cochran EJ, Leurgans S, Wuu J, et al. Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol. 2002;443:136–53.PubMedCrossRef
95.
Chen H-K, Ji Z-S, Dodson SE, Miranda RD, Rosenblum CI, Reynolds IJ, et al. Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J Biol Chem. 2011;286:5215–21.PubMedCrossRef
96.
Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A. 2013;110:20284–9.PubMedPubMedCentralCrossRef
97.
Bunker JM, Wilson L, Jordan MA, Feinstein SC. Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration. Mol Biol Cell. 2004;15(6):2720–728. doi:10.​1091/​mbc.​E04-01-0062.
98.
Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med. 2009;15:112–9.PubMedCrossRef
99.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005;309:476–81.PubMedPubMedCentralCrossRef
100.
Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, et al. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol. 2006;168:1598–607.PubMedPubMedCentralCrossRef
101.
Lee H-K, Velazquez Sanchez C, Chen M, Morin PJ, Wells JM, Hanlon EB, et al. Three dimensional human neuro-spheroid model of Alzheimer’s disease based on differentiated induced pluripotent stem cells. PLoS One. 2016;11:e0163072.PubMedPubMedCentralCrossRef
102.
Zhang D, Pekkanen-Mattila M, Shahsavani M, Falk A, Teixeira AI, Herland A. A 3D Alzheimer’s disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons. Biomaterials. 2014;35:1420–8.PubMedCrossRef
103.
Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 1989;8:393–9.PubMedPubMedCentral
104.
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–26.PubMedCrossRef
105.
Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry. 1992;31:10626–33.PubMedCrossRef
106.
Connell JW, Rodriguez-Martin T, Gibb GM, Kahn NM, Grierson AJ, Hanger DP, et al. Quantitative analysis of tau isoform transcripts in sporadic tauopathies. Brain Res Mol Brain Res. 2005;137:104–9.PubMedCrossRef
107.
Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, et al. 5’ splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem. 1999;274:15134–43.PubMedCrossRef
108.
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33:95–130.PubMedCrossRef
109.
Lacovich V, Espindola SL, Alloatti M, Pozo Devoto V, Cromberg LE, Čarná ME, et al. Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. J Neurosci. 2017;37:58–69.PubMedCrossRef
110.
Sposito T, Preza E, Mahoney CJ, Setó-Salvia N, Ryan NS, Morris HR, et al. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet. 2015;24:5260–9.PubMedPubMedCentralCrossRef
111.
Wren MC, Zhao J, Liu C-C, Murray ME, Atagi Y, Davis MD, et al. Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener. 2015;10:46.PubMedPubMedCentralCrossRef
112.
Iovino M, Agathou S, González-Rueda A, Del Castillo V-HM, Borroni B, Alberici A, et al. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain. 2015;138:3345–59.PubMedPubMedCentralCrossRef
113.
Imamura K, Sahara N, Kanaan NM, Tsukita K, Kondo T, Kutoku Y, et al. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons. Sci Rep. 2016;6:34904.PubMedPubMedCentralCrossRef
114.
Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell. 2013;13:691–705.PubMedPubMedCentralCrossRef
115.
Vera E, Bosco N, Studer L. Generating late-onset human iPSC-based disease models by inducing neuronal age-related phenotypes through telomerase manipulation. Cell Rep. 2016;17:1184–92.PubMedPubMedCentralCrossRef
116.
Espuny-Camacho I, Arranz AM, Fiers M, Snellinx A, Ando K, Munck S, et al. Hallmarks of Alzheimer’s disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron. 2017;93:1066–1081.e8.PubMedCrossRef
117.
Verheyen A, Diels A, Dijkmans J, Oyelami T, Meneghello G, Mertens L, et al. Using human iPSC-derived neurons to model TAU aggregation. PLoS One. 2015;10:e0146127.PubMedPubMedCentralCrossRef
118.
Usenovic M, Niroomand S, Drolet RE, Yao L, Gaspar RC, Hatcher NG, et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J Neurosci. 2015;35:14234–50.PubMedCrossRef
119.
Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–92.PubMedPubMedCentralCrossRef
120.
Kovacs GG, Wöhrer A, Ströbel T, Botond G, Attems J, Budka H. Unclassifiable tauopathy associated with an A152T variation in MAPT exon 7. Clin Neuropathol. 2011;30:3–10.PubMedCrossRef
121.
Kara E, Ling H, Pittman AM, Shaw K, de Silva R, Simone R, et al. The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features. Neurobiol Aging. 2012;33:2231.e7–2231.e14.CrossRef
122.
Coppola G, Chinnathambi S, Lee JJ, Dombroski BA, Baker MC, Soto-Ortolaza AI, et al. Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer’s diseases. Hum Mol Genet. 2012;21:3500–12.PubMedPubMedCentralCrossRef
123.
Silva MC, Cheng C, Mair W, Almeida S, Fong H, Biswas MHU, et al. Human iPSC-derived neuronal model of tau-A152T frontotemporal dementia reveals tau-mediated mechanisms of neuronal vulnerability. Stem Cell Rep. 2016;7:325–40.CrossRef
124.
Biswas MHU, Almeida S, Lopez-Gonzalez R, Mao W, Zhang Z, Karydas A, et al. MMP-9 and MMP-2 contribute to neuronal cell death in iPSC models of frontotemporal dementia with MAPT mutations. Stem Cell Rep. 2016;7:316–24.CrossRef
125.
Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of a-synucleinopathy. PLoS One. 2010;5(2):e9313.
126.
Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, et al. Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010;330:198.PubMedPubMedCentralCrossRef
127.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science. 2007;316:750–4.PubMedCrossRef
128.
Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77:43–51.PubMedCrossRef
129.
Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93.PubMedPubMedCentralCrossRef
130.
131.
Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016;22:1358–67.PubMedPubMedCentralCrossRef
132.
Pandya H, Shen MJ, Ichikawa DM, Sedlock AB, Choi Y, Johnson KR, et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. 2017. p. 2–11.
133.
Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, et al. iPSC-derived human microglia-like cells to study neurological diseases highlights. Neuron. 2017;94:278–93.PubMedCrossRef
134.
Erickson MA, Banks WA. Blood–brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J Cereb Blood Flow Metab. 2013;33:1500–13.PubMedPubMedCentralCrossRef
135.
Minami H, Tashiro K, Okada A, Hirata N, Yamaguchi T, Takayama K, et al. Generation of brain microvascular endothelial-like cells from human induced pluripotent stem cells by co-culture with C6 glioma Cells. PLoS One. 2015;10:e0128890.PubMedPubMedCentralCrossRef
136.
Williams CA, Lavik EB, Manuscript A, Amini AR, Laurencin CT, Nukavarapu SP, et al. Engineering the human pluripotent stem cell microenvironment to direct cell fate. Nat Biotechnol. 2012;30:2014.
137.
Yamamizu K, Iwasaki M, Takakubo H, Sakamoto T, Ikuno T, Miyoshi M, et al. In vitro modeling of blood-brain barrier with human iPSC-derived endothelial cells, pericytes, neurons, and astrocytes via Notch signaling. Stem Cell Rep. 2017;8:634–47.CrossRef
138.
Azevedo FAC, Carvalho LRB, Grinberg LT, Farfel JM, Ferretti REL, Leite REP, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009;513:532–41.PubMedCrossRef
139.
Johnson MA, Weick JP, Pearce RA, Zhang S-C. Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci. 2007;27:3069–77.PubMedPubMedCentralCrossRef
140.
Verkhratsky A, Olabarria M, Noristani HN, Yeh C-Y, Rodriguez JJ. Astrocytes in Alzheimer’s disease. Neurotherapeutics. 2010;7(4):399–412.
141.
Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L, Ladjevardi S, et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell. 2015;17:705–18.PubMedCrossRef
142.
143.
Hibaoui Y, Grad I, Letourneau A, Sailani MR, Dahoun S, Santoni FA, et al. Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21. EMBO Mol Med. 2014;6:259–77.PubMed
144.
Kunio M, Yang C, Minakuchi Y, Ohori K, Soutome M, Hirasawa T, et al. Comparison of genomic and epigenomic expression in monozygotic twins discordant for Rett syndrome. PLoS One. 2013;8:e66729.PubMedCentralCrossRef
145.
Woodard CMM, Campos BAA, Kuo S-H, Nirenberg MJJ, Nestor MWW, Zimmer M, et al. iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson’s disease. Cell Rep. 2014;9:1173–82.PubMedPubMedCentralCrossRef
146.
Hendriks WT, Warren CR, Cowan CA. Genome editing in human pluripotent stem cells: approaches, pitfalls, and solutions. Cell Stem Cell. 2016;18:53–65.PubMedPubMedCentralCrossRef
147.
Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver RC, et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol. 2009;27:851–7.PubMedPubMedCentralCrossRef
148.
Zou J, Maeder ML, Mali P, Pruett-Miller SM, Thibodeau-Beganny S, Chou B-K, et al. Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell. 2009;5:97–110.PubMedPubMedCentralCrossRef
149.
Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326:1509–12.PubMedCrossRef
150.
151.
152.
Huang Y-WA, Zhou B, Wernig M, Südhof TCTC. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell. 2017;168(3):427–41.e21.
153.
Hossini AM, Megges M, Prigione A, Lichtner B, Toliat MR, Wruck W, et al. Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer’s disease donor as a model for investigating AD-associated gene regulatory networks. BMC Genomics. 2015;16:84
Metadata
Title
Stem cell models of Alzheimer’s disease: progress and challenges
Publication date
01-12-2017
Published in
Alzheimer's Research & Therapy / Issue 1/2017
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-017-0268-4

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