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Stem Cell Genetics for Biomedical Research pp 3–12Cite as

Human-Induced Pluripotent Stem Cell-Derived Neurons to Model and Gain Insights into Alzheimer’s Disease Pathogenesis

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Abstract

Alzheimer’s disease (AD) is the most common adult neurodegenerative disorder with the projected number of patients increasing to over 100 million in the next decades. Currently, there is no treatment that stops the progression of AD. Like other complex disorders, modeling AD in the laboratory is challenging due to inaccessibility of relevant living tissue, unknown interactions between genetics and environment, and species-specific differences between animal models and human subjects. Human induced pluripotent stem cell (hiPSC) technology has revolutionized the field of complex disease modeling. With this system, unique patient genetic backgrounds are captured in the dish and the cells can be directly differentiated to any cell type of an organism, including central nervous system cells affected in AD. This methodology allows for the design of genetic, molecular and biochemical experiments to decipher the complexity of AD using human neurons, or other CNS cell types, in the laboratory. Here we review current models of AD using hiPSCs, discuss advantages and disadvantages to the system, and propose future directions for this technology.

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References

  1. Wimo A et al (2017) The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement J Alzheimers Assoc 13(1):1–7

    Article  Google Scholar 

  2. Jack CR Jr et al (2010) Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain 133(11):3336–3348

    Article  PubMed  PubMed Central  Google Scholar 

  3. Reiman EM et al (2012) Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol 11(12):1048–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mandelkow EM, Mandelkow E (1998) Tau in Alzheimer’s disease. Trends Cell Biol 8(11):425–427

    Article  CAS  PubMed  Google Scholar 

  5. Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6(4):487–498

    Article  CAS  PubMed  Google Scholar 

  6. Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement J Alzheimers Assoc 12(6):733–748

    Article  Google Scholar 

  7. Sullivan SE, Young-Pearse TL (2017) Induced pluripotent stem cells as a discovery tool for Alzheimers disease. Brain Res 1656:98–106

    Article  CAS  PubMed  Google Scholar 

  8. Wojda U, Kuznicki J (2013) Alzheimer’s disease modeling: ups, downs, and perspectives for human induced pluripotent stem cells. J Alzheimers Dis 34(3):563–588

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  CAS  PubMed  Google Scholar 

  11. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  CAS  PubMed  Google Scholar 

  12. Mungenast AE, Siegert S, Tsai LH (2016) Modeling Alzheimer’s disease with human induced pluripotent stem (iPS) cells. Mol Cell Neurosci 73:13–31

    Article  CAS  PubMed  Google Scholar 

  13. Yagi T et al (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20(23):4530–4539

    Article  CAS  PubMed  Google Scholar 

  14. De Strooper B, Iwatsubo T, Wolfe MS (2012) Presenilins and gamma-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med 2(1):a006304

    Article  PubMed  PubMed Central  Google Scholar 

  15. Israel MA et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482(7384):216–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cataldo AM et al (2008) Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am J Pathol 173(2):370–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cataldo AM et al (2004) Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J Neuropathol Exp Neurol 63(8):821–830

    Article  CAS  PubMed  Google Scholar 

  18. Cataldo AM et al (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(1):277–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kondo T et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12(4):487–496

    Article  CAS  PubMed  Google Scholar 

  20. Shankar GM et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Muratore CR et al (2014) The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23(13):3523–3536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Muratore CR et al (2017) Cell-type dependent Alzheimer’s disease phenotypes: probing the biology of selective neuronal vulnerability. Stem Cell Reports 9(6):1868–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sproul AA et al (2014) Characterization and molecular profiling of PSEN1 familial Alzheimer’s disease iPSC-derived neural progenitors. PLoS One 9(1):e84547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Woodruff G et al (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 Reports 5(4):974–985

    Article  CAS  PubMed  Google Scholar 

  25. Anonymous (2007) Alzheimer research forum discussion: gain or loss of function – time to shake up assumptions on gamma-secretase in Alzheimer disease? J Alzheimers Dis 11(3):399–417

    Article  Google Scholar 

  26. Ortiz-Virumbrales M et al (2017) CRISPR/Cas9-correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 (N141I) neurons. Acta Neuropathol Commun 5(1):77

    Article  PubMed  PubMed Central  Google Scholar 

  27. Choi SH et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515(7526):274–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Raja WK et al (2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS One 11(9):e0161969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA (1996) Abnormalities of the endosomal-lysosomal system in Alzheimer’s disease: relationship to disease pathogenesis. Adv Exp Med Biol 389:271–280

    Article  CAS  PubMed  Google Scholar 

  30. Avramopoulos D (2009) Genetics of Alzheimer’s disease: recent advances. Genome Med 1(3):34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Duan L et al (2014) Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death. Mol Neurodegener 9:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Young JE et al (2015) Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell 16(4):373–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Small SA, Simoes-Spassov S, Mayeux R, Petsko GA (2017) Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer’s disease. Trends Neurosci 40(10):592–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Willnow TE, Andersen OM (2013) Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease. J Cell Sci 126(Pt 13):2751–2760

    Article  CAS  PubMed  Google Scholar 

  35. Hossini AM et al (2015) 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 16:84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brownjohn PW et al (2017) Phenotypic screening identifies modulators of amyloid precursor protein processing in human stem cell models of Alzheimer’s disease. Stem Cell Reports 8(4):870–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu Q et al (2014) Effect of potent gamma-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol 71(12):1481–1489

    Article  PubMed  PubMed Central  Google Scholar 

  38. Medda X et al (2016) Development of a scalable, high-throughput-compatible assay to detect tau aggregates using iPSC-derived cortical neurons maintained in a three-dimensional culture format. J Biomol Screen 21(8):804–815

    Article  CAS  PubMed  Google Scholar 

  39. Rigamonti A et al (2016) Large-scale production of mature neurons from human pluripotent stem cells in a three-dimensional suspension culture system. Stem Cell Reports 6(6):993–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Huh CJ et al (2016) Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. Elife 5:pii: e18648

    Article  Google Scholar 

  41. Mertens J et al (2015) Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17(6):705–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vierbuchen T et al (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tcw J et al (2017) An efficient platform for astrocyte differentiation from human induced pluripotent stem cells. Stem Cell Reports 9(2):600–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ehrlich M et al (2017) Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors. Proc Natl Acad Sci U S A 114(11):E2243–E2252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Abud EM et al (2017) iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94(2):278–293. e279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pathology, University of Washington, Seattle, WA, USA

    Jessica E. Young

  2. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA

    Jessica E. Young

  3. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain

    Raul Delgado-Morales

  4. Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands

    Raul Delgado-Morales

Authors
  1. Jessica E. Young
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  2. Raul Delgado-Morales
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Corresponding author

Correspondence to Jessica E. Young .

Editor information

Editors and Affiliations

  1. Duran i Reynals Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

    Raul Delgado-Morales

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Young, J.E., Delgado-Morales, R. (2018). Human-Induced Pluripotent Stem Cell-Derived Neurons to Model and Gain Insights into Alzheimer’s Disease Pathogenesis. In: Delgado-Morales, R. (eds) Stem Cell Genetics for Biomedical Research. Springer, Cham. https://doi.org/10.1007/978-3-319-90695-9_1

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