Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Three-dimensional modeling of human neurodegeneration: brain organoids coming of age

Molecular Psychiatry volume 25, pages 254–274 (2020)Cite this article

Subjects

Abstract

The prevalence of dementia and other neurodegenerative diseases is rapidly increasing in aging nations. These relentless and progressive diseases remain largely without disease-modifying treatments despite decades of research and investments. It is becoming clear that traditional two-dimensional culture and animal model systems, while providing valuable insights on the major pathophysiological pathways associated with these diseases, have not translated well to patients’ bedside. Fortunately, the advent of induced-pluripotent stem cells and three-dimensional cell culture now provide tools that are revolutionizing the study of human diseases by permitting analysis of patient-derived human tissue with non-invasive procedures. Specifically, brain organoids, self-organizing neural structures that can mimic human fetal brain development, have now been harnessed to develop alternative models of Alzheimer’s disease, Parkinson’s disease, motor neuron disease, and Frontotemporal dementia by recapitulating important neuropathological hallmarks found in these disorders. Despite these early breakthroughs, several limitations need to be vetted in brain organoid models in order to more faithfully match human tissue qualities, including relative tissue immaturity, lack of vascularization and incomplete cellular diversity found in this culture system. Here, we review current brain organoid protocols, the pathophysiology of neurodegenerative disorders, and early studies with brain organoid neurodegeneration models. We then discuss the multiple engineering and conceptual challenges surrounding their use and provide possible solutions and exciting avenues to be pursued. Altogether, we believe that brain organoids models, improved with classical and emerging molecular and analytic tools, have the potential to unravel the opaque pathophysiological mechanisms of neurodegeneration and devise novel treatments for an array of neurodegenerative disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Fiest KM, Jette N, Roberts JI, Maxwell CJ, Smith EE, Black SE, et al. The prevalence and incidence of dementia: a systematic review and meta-analysis. Can J Neurol Sci Le J Can Sci Neurol. 2016;43(Suppl 1):S3–S50.

    Article  Google Scholar 

  2. Wong SL, Gilmour H, Ramage-Morin PL. Alzheimer's disease and other dementias in Canada. Health Rep. 2016;27:11–16.

    PubMed  Google Scholar 

  3. 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;20:385–96 e383.

    Article  CAS  PubMed  Google Scholar 

  4. Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014;9:2329–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hansen DV, Lui JH, Parker PR, Kriegstein AR. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature. 2010;464:554–61.

    Article  CAS  PubMed  Google Scholar 

  6. Lui JH, Nowakowski TJ, Pollen AA, Javaherian A, Kriegstein AR, Oldham MC. Radial glia require PDGFD-PDGFRbeta signalling in human but not mouse neocortex. Nature. 2014;515:264–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Matsui TK, Matsubayashi M, Sakaguchi YM, Hayashi RK, Zheng C, Sugie K, et al. Six-month cultured cerebral organoids from human ES cells contain matured neural cells. Neurosci Lett. 2018;670:75–82.

    Article  CAS  PubMed  Google Scholar 

  8. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–9.

    Article  CAS  PubMed  Google Scholar 

  9. Pasca 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xiang Y, Tanaka Y, Patterson B, Kang YJ, Govindaiah G, Roselaar N, et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell. 2017;21:383–98 e387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Krefft O, Jabali A, Iefremova V, Koch P, Ladewig J. Generation of standardized and reproducible forebrain-type cerebral organoids from human induced pluripotent stem cells. J Vis Exp: JoVE. 2018;131:56768.

  12. Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472:51–56.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran HD, Goke 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Monzel AS, Smits LM, Hemmer K, Hachi S, Moreno EL, van Wuellen T, et al. Derivation of human midbrain-specific organoids from neuroepithelial stem cells. Stem Cell Rep. 2017;8:1144–54.

    Article  CAS  Google Scholar 

  17. Qian X, Jacob F, Song MM, Nguyen HN, Song H, Ming GL. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc. 2018;13:565–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Muguruma K, Nishiyama A, Ono Y, Miyawaki H, Mizuhara E, Hori S, et al. Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nat Neurosci. 2010;13:1171–80.

    Article  CAS  PubMed  Google Scholar 

  19. Kawada J, Kaneda S, Kirihara T, Maroof A, Levi T, Eggan K, et al. Generation of a motor nerve organoid with human stem cell-derived neurons. Stem Cell Rep. 2017;9:1441–9.

    Article  Google Scholar 

  20. Hor JH, Soh ES, Tan LY, Lim VJW, Santosa MM, Winanto, et al. Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy. Cell Death Dis. 2018;9:1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M, et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun. 2015;6:8896.

    Article  CAS  PubMed  Google Scholar 

  22. Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017;18:573–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stachowiak EK, Benson CA, Narla ST, Dimitri A, Chuye LEB, Dhiman S, et al. Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1. Transl Psychiatry. 2017;7:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Johnstone M, Vasistha NA, Barbu MC, Dando O, Burr K, Christopher E, et al. Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFkappaB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging. Mol psychiatry. 2019;24:294–311.

    Article  CAS  PubMed  Google Scholar 

  25. Qian X, Nguyen HN, Jacob F, Song H, Ming GL. Using brain organoids to understand Zika virus-induced microcephaly. Development. 2017;144:952–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mellios N, Feldman DA, Sheridan SD, Ip JPK, Kwok S, Amoah SK, et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol psychiatry. 2018;23:1051–65.

    Article  CAS  PubMed  Google Scholar 

  27. Mellios N, Feldman DA, Sheridan SD, Ip JPK, Kwok S, Amoah SK, et al. Human cerebral organoids reveal deficits in neurogenesis and neuronal migration in MeCP2-deficient neural progenitors. Mol psychiatry. 2018;23:791.

    Article  Google Scholar 

  28. Dakic V, Minardi Nascimento J, Costa Sartore R, Maciel RM, de Araujo DB, Ribeiro S, et al. Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Sci Rep. 2017;7:12863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Kleinman HK, McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW, et al. Basement membrane complexes with biological activity. Biochemistry. 1986;25:312–8.

    Article  CAS  PubMed  Google Scholar 

  31. Li R, Sun L, Fang A, Li P, Wu Q, Wang X. Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease. Protein Cell. 2017;8:823–33.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 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;20:435–49 e434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Double KL, Halliday GM, Kril JJ, Harasty JA, Cullen K, Brooks WS, et al. Topography of brain atrophy during normal aging and Alzheimer's disease. Neurobiol aging. 1996;17:513–21.

    Article  CAS  PubMed  Google Scholar 

  34. Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, et al. Brain atrophy in Alzheimer's disease and aging. Ageing Res Rev. 2016;30:25–48.

    Article  PubMed  Google Scholar 

  35. Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, et al. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci : Off J Soc Neurosci. 2010;30:7507–15.

    Article  CAS  Google Scholar 

  36. Xekardaki A, Kovari E, Gold G, Papadimitropoulou A, Giacobini E, Herrmann F, et al. Neuropathological changes in aging brain. Adv Exp Med Biol. 2015;821:11–17.

    Article  PubMed  Google Scholar 

  37. Kovacs GG, Lee VM, Trojanowski JQ. Protein astrogliopathies in human neurodegenerative diseases and aging. Brain Pathol. 2017;27:675–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kovacs GG, Milenkovic I, Wohrer A, Hoftberger R, Gelpi E, Haberler C, et al. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol. 2013;126:365–84.

    Article  CAS  PubMed  Google Scholar 

  39. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006;66:1837–44.

    Article  CAS  PubMed  Google Scholar 

  40. Mattson MP, Arumugam TV. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 2018;27:1176–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ioannidou A, Goulielmaki E, Garinis GA. DNA damage: from chronic inflammation to age-related deterioration. Front Genet. 2016;7:187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chow HM, Herrup K. Genomic integrity and the ageing brain. Nat Rev Neurosci. 2015;16:672–84.

    Article  CAS  PubMed  Google Scholar 

  43. Madabhushi R, Pan L, Tsai LH. DNA damage and its links to neurodegeneration. Neuron. 2014;83:266–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McKinnon PJ. Maintaining genome stability in the nervous system. Nat Neurosci. 2013;16:1523–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. d'Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8:512–22.

    Article  CAS  PubMed  Google Scholar 

  46. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK. Cellular senescence and the aging brain. Exp Gerontol. 2015;68:3–7.

    Article  CAS  PubMed  Google Scholar 

  47. van der Horst GT, van Steeg H, Berg RJ, van Gool AJ, de Wit J, Weeda G, et al. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell. 1997;89:425–35.

    Article  PubMed  Google Scholar 

  48. Andressoo JO, Weeda G, de Wit J, Mitchell JR, Beems RB, van Steeg H, et al. An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair. Mol Cell Biol. 2009;29:1276–90.

    Article  CAS  PubMed  Google Scholar 

  49. Laposa RR, Huang EJ, Cleaver JE. Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci USA. 2007;104:1389–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kuljis RO, Xu Y, Aguila MC, Baltimore D. Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia. Proc Natl Acad Sci USA. 1997;94:12688–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Adamec E, Vonsattel JP, Nixon RA. DNA strand breaks in Alzheimer's disease. Brain Res. 1999;849:67–77.

    Article  CAS  PubMed  Google Scholar 

  52. Jacobsen E, Beach T, Shen Y, Li R, Chang Y. Deficiency of the Mre11 DNA repair complex in Alzheimer's disease brains. Brain Res Mol Brain Res. 2004;128:1–7.

    Article  CAS  PubMed  Google Scholar 

  53. Shackelford DA. DNA end joining activity is reduced in Alzheimer's disease. Neurobiol aging. 2006;27:596–605.

    Article  CAS  PubMed  Google Scholar 

  54. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38:515–7.

    Article  CAS  PubMed  Google Scholar 

  55. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet. 2006;38:518–20.

    Article  CAS  PubMed  Google Scholar 

  56. Kisby GE, Milne J, Sweatt C. Evidence of reduced DNA repair in amyotrophic lateral sclerosis brain tissue. Neuroreport. 1997;8:1337–40.

    Article  CAS  PubMed  Google Scholar 

  57. Kikuchi H, Furuta A, Nishioka K, Suzuki SO, Nakabeppu Y, Iwaki T. Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis. Acta Neuropathol. 2002;103:408–14.

    Article  CAS  PubMed  Google Scholar 

  58. Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997;69:2064–74.

    Article  CAS  PubMed  Google Scholar 

  59. Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, et al. Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet. 2007;16:1604–18.

    Article  CAS  PubMed  Google Scholar 

  60. Qian M, Liu Z, Peng L, Tang X, Meng F, Ao Y, et al. Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria. Elife. 2018;7:e34836.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–95.

    Article  CAS  PubMed  Google Scholar 

  62. Roberts RF, Tang MY, Fon EA, Durcan TM. Defending the mitochondria: the pathways of mitophagy and mitochondrial-derived vesicles. Int J Biochem cell Biol. 2016;79:427–36.

    Article  CAS  PubMed  Google Scholar 

  63. Matheoud D, Sugiura A, Bellemare-Pelletier A, Laplante A, Rondeau C, Chemali M, et al. Parkinson's disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation. Cell. 2016;166:314–27.

    Article  CAS  PubMed  Google Scholar 

  64. Helley MP, Pinnell J, Sportelli C, Tieu K. Mitochondria: a common target for genetic mutations and environmental toxicants in Parkinson's disease. Front Genet. 2017;8:177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Deger JM, Gerson JE, Kayed R. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging cell. 2015;14:715–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Baker MJ, Palmer CS, Stojanovski D. Mitochondrial protein quality control in health and disease. Br J Pharm. 2014;171:1870–89.

    Article  CAS  Google Scholar 

  67. Misgeld T, Schwarz TL. Mitostasis in neurons: maintaining mitochondria in an extended cellular architecture. Neuron. 2017;96:651–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Scrivo A, Bourdenx M, Pampliega O, Cuervo AM. Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol. 2018;17:802–15.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Hewitt G, Korolchuk VI. Repair, reuse, recycle: the expanding role of autophagy in genome maintenance. Trends Cell Biol. 2017;27:340–51.

    Article  CAS  PubMed  Google Scholar 

  70. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233:6425–40.

    Article  CAS  PubMed  Google Scholar 

  71. Caplan IF, Maguire-Zeiss KA. Toll-like receptor 2 signaling and current approaches for therapeutic modulation in synucleinopathies. Front Pharm. 2018;9:417.

    Article  CAS  Google Scholar 

  72. Gambuzza ME, Sofo V, Salmeri FM, Soraci L, Marino S, Bramanti P. Toll-like receptors in Alzheimer's disease: a therapeutic perspective. CNS Neurol Disord Drug Targets. 2014;13:1542–58.

    Article  CAS  PubMed  Google Scholar 

  73. ElAli A, Rivest S. Microglia in Alzheimer's disease: a multifaceted relationship. Brain, Behav, Immun. 2016;55:138–50.

    Article  CAS  Google Scholar 

  74. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21:1359–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jaworski T, Dewachter I, Lechat B, Gees M, Kremer A, Demedts D, et al. GSK-3alpha/beta kinases and amyloid production in vivo. Nature. 2011;480:E4–5. discussion E6

    Article  CAS  PubMed  Google Scholar 

  77. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423:435–9.

    Article  CAS  PubMed  Google Scholar 

  78. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. New Engl J Med. 2014;370:322–33.

    Article  CAS  PubMed  Google Scholar 

  79. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. New Engl J Med. 2013;369:341–50.

    Article  CAS  PubMed  Google Scholar 

  80. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. New Engl J Med. 2014;370:311–21.

    Article  CAS  PubMed  Google Scholar 

  81. Lee HK, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Amiri A, Coppola G, Scuderi S, Wu F, Roychowdhury T, Liu F, et al. Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science. 2018;362:eaat6720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Raja WK, Mungenast AE, Lin YT, 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:e0161969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA. 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. 2000;157:277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cataldo A, Rebeck GW, Ghetri B, Hulette C, Lippa C, Van Broeckhoven C, et al. Endocytic disturbances distinguish among subtypes of Alzheimer's disease and related disorders. Ann Neurol. 2001;50:661–5.

    Article  CAS  PubMed  Google Scholar 

  86. Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer's disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98:1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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.

    Article  CAS  PubMed  Google Scholar 

  88. Lambert JC, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Park J, Wetzel I, Marriott I, Dreau D, D'Avanzo C, Kim DY, et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci. 2018;21:941–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Seo J, Kritskiy O, Watson LA, Barker SJ, Dey D, Raja WK, et al. Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J Neurosci : Off J Soc Neurosci. 2017;37:9917–24.

    Article  CAS  Google Scholar 

  91. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol aging. 2003;24:197–211.

    Article  PubMed  Google Scholar 

  92. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128:805–20.

    Article  PubMed  Google Scholar 

  94. Lionnet A, Leclair-Visonneau L, Neunlist M, Murayama S, Takao M, Adler CH, et al. Does Parkinson's disease start in the gut? Acta Neuropathol. 2018;135:1–12.

    Article  PubMed  Google Scholar 

  95. Son MY, Sim H, Son YS, Jung KB, Lee MO, Oh JH, et al. Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient-derived induced pluripotent stem cells. Neuropathol Appl Neurobiol. 2017;43:584–603.

    Article  CAS  PubMed  Google Scholar 

  96. Kim H, Park HJ, Choi H, Chang Y, Park H, Shin J, et al. Modeling G2019S-LRRK2 sporadic Parkinson's disease in 3D midbrain organoids. Stem Cell Rep. 2019;12:518–31.

    Article  CAS  Google Scholar 

  97. Smits LM, Reinhardt L, Reinhardt P, Glatza M, Monzel AS, Stanslowsky N, et al. Modeling Parkinson's disease in midbrain-like organoids. NPJ Park's Dis. 2019;5:5.

    Article  Google Scholar 

  98. Surmeier DJ. Determinants of dopaminergic neuron loss in Parkinson's disease. FEBS J. 2018;285:3657–68.

  99. Rund BR. Is there a degenerative process going on in the brain of people with Schizophrenia? Front Hum Neurosci. 2009;3:36.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Marion RM, Strati K, Li H, Tejera A, Schoeftner S, Ortega S, et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell. 2009;4:141–54.

    Article  CAS  PubMed  Google Scholar 

  101. Suhr ST, Chang EA, Tjong J, Alcasid N, Perkins GA, Goissis MD, et al. Mitochondrial rejuvenation after induced pluripotency. PloS ONE. 2010;5:e14095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Brauninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA. 2015;112:15672–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Luo C, Lancaster MA, Castanon R, Nery JR, Knoblich JA, Ecker JR. Cerebral organoids recapitulate epigenomic signatures of the human fetal brain. Cell Rep. 2016;17:3369–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yoon KJ, Ringeling FR, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D, et al. Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell. 2017;171:877–89 e817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Jin K. Modern biological theories of aging. Aging Dis. 2010;1:72–74.

    PubMed  PubMed Central  Google Scholar 

  107. Guillaumet-Adkins A, Yanez Y, Peris-Diaz MD, Calabria I, Palanca-Ballester C, Sandoval J. Epigenetics and oxidative stress in aging. Oxid Med Cell Longev. 2017;2017:9175806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Agarwal S, Loh YH, McLoughlin EM, Huang J, Park IH, Miller JD, et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature. 2010;464:292–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Batista LF, Pech MF, Zhong FL, Nguyen HN, Xie KT, Zaug AJ, et al. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature. 2011;474:399–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Andrade LN, Nathanson JL, Yeo GW, Menck CF, Muotri AR. Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome. Hum Mol Genet. 2012;21:3825–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mertens J, Paquola ACM, Ku M, Hatch E, Bohnke 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang C, Skamagki M, Liu Z, Ananthanarayanan A, Zhao R, Li H, et al. Biological significance of the suppression of oxidative phosphorylation in induced pluripotent stem cells. Cell Rep. 2017;21:2058–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tang Y, Liu ML, Zang T, Zhang CL. Direct reprogramming rather than iPSC-based reprogramming maintains aging hallmarks in human motor neurons. Front Mol Neurosci. 2017;10:359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lin L, Goke J, Cukuroglu E, Dranias MR, VanDongen AM, Stanton LW. Molecular Features underlying neurodegeneration identified through in vitro modeling of genetically diverse Parkinson's disease patients. Cell Rep. 2016;15:2411–26.

    Article  CAS  PubMed  Google Scholar 

  115. Garcia TY, Gutierrez M, Reynolds J, Lamba DA. Modeling the dynamic AMD-associated chronic oxidative stress changes in human ESC and iPSC-derived RPE cells. Invest Ophthalmol Vis Sci. 2015;56:7480–8.

    Article  CAS  PubMed  Google Scholar 

  116. Schwartz MP, Hou Z, Propson NE, Zhang J, Engstrom CJ, Santos Costa V, et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci USA. 2015;112:12516–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dezonne RS, Sartore RC, Nascimento JM, Saia-Cereda VM, Romao LF, Alves-Leon SV, et al. Derivation of functional human astrocytes from cerebral organoids. Sci Rep. 2017;7:45091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sloan SA, Darmanis S, Huber N, Khan TA, Birey F, Caneda C, et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron. 2017;95:779–90 e776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lancaster MA, Corsini NS, Wolfinger S, Gustafson EH, Phillips AW, Burkard TR, et al. Guided self-organization and cortical plate formation in human brain organoids. Nat Biotechnol. 2017;35:659–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ormel PR, Vieira de Sa R, van Bodegraven EJ, Karst H, Harschnitz O, Sneeboer MAM, et al. Microglia innately develop within cerebral organoids. Nat Commun. 2018;9:4167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bagley JA, Reumann D, Bian S, Levi-Strauss J, Knoblich JA. Fused cerebral organoids model interactions between brain regions. Nat methods. 2017;14:743–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Birey F, Andersen J, Makinson CD, Islam S, Wei W, Huber N, et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017;545:54–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Aach J, Lunshof J, Iyer E, Church GM Addressing the ethical issues raised by synthetic human entities with embryo-like features. Elife 2017;6:e20674.

  124. Munsie M, Hyun I, Sugarman J. Ethical issues in human organoid and gastruloid research. Development. 2017;144:942–5.

    Article  CAS  PubMed  Google Scholar 

  125. Vera E, Studer L. When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease. Development. 2015;142:3085–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Quadrato G, Nguyen T, Macosko EZ, Sherwood JL, Min Yang S, Berger DR, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature. 2017;545:48–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Giandomenico SL, Mierau SB, Gibbons GM, Wenger LMD, Masullo L, Sit T, et al. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat Neurosci. 2019;22:669–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hartley BJ, Brennand KJ. Neural organoids for disease phenotyping, drug screening and developmental biology studies. Neurochem Int. 2017;106:85–93.

    Article  CAS  PubMed  Google Scholar 

  129. Rigamonti A, Repetti GG, Sun C, Price FD, Reny DC, Rapino F, et al. Large-scale production of mature neurons from human pluripotent stem cells in a three-dimensional suspension culture system. Stem Cell Rep. 2016;6:993–1008.

    Article  CAS  Google Scholar 

  130. Yoon SJ, Elahi LS, Pasca AM, Marton RM, Gordon A, Revah O, et al. Reliability of human cortical organoid generation. Nat methods. 2019;16:75–78.

    Article  CAS  PubMed  Google Scholar 

  131. Lange C, Turrero Garcia M, Decimo I, Bifari F, Eelen G, Quaegebeur A, et al. Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J. 2016;35:924–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Vasudevan A, Long JE, Crandall JE, Rubenstein JL, Bhide PG. Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nat Neurosci. 2008;11:429–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Takebe T, Enomura M, Yoshizawa E, Kimura M, Koike H, Ueno Y, et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell. 2015;16:556–65.

    Article  CAS  PubMed  Google Scholar 

  134. Mansour AA, Goncalves JT, Bloyd CW, Li H, Fernandes S, Quang D, et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol. 2018;36:432–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Archer TC, Ehrenberger T, Mundt F, Gold MP, Krug K, Mah CK, et al. Proteomics, post-translational modifications, and integrative analyses reveal molecular heterogeneity within medulloblastoma subgroups. Cancer Cell. 2018;34:396–410 e398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Djuric U, Zadeh G, Aldape K, Diamandis P. Precision histology: how deep learning is poised to revitalize histomorphology for personalized cancer care. NPJ Precis Oncol. 2017;1:22.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Djuric U, Rodrigues DC, Batruch I, Ellis J, Shannon P, Diamandis P. Spatiotemporal proteomic profiling of human cerebral development. Mol Cell Proteom : MCP. 2017;16:1548–62.

    Article  CAS  Google Scholar 

  138. Coudray N, Ocampo PS, Sakellaropoulos T, Narula N, Snuderl M, Fenyo D, et al. Classification and mutation prediction from non-small cell lung cancer histopathology images using deep learning. Nat Med. 2018;24:1559–67.

    Article  CAS  PubMed  Google Scholar 

  139. Papaioannou MD, Djuric U, Kao J, Karimi S, Zadeh G, Aldape K et al. Proteomic analysis of meningiomas reveals clinically-distinct molecular patterns. Neuro Oncol. 2019;21:1028–38.

  140. Vasaikar S, Huang C, Wang X, Petyuk VA, Savage SR, Wen B, et al. Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities. Cell. 2019;177:1035–49 e1019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhang H, Liu T, Zhang Z, Payne SH, Zhang B, McDermott JE, et al. Integrated proteogenomic characterization of human high-grade serous ovarian cancer. Cell. 2016;166:755–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016;534:55–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Xie Q, Faust K, Van Ommeren R, Sheikh A, Djuric U, Diamandis P. Deep learning for image analysis: personalizing medicine closer to the point of care. Crit Rev Clin Lab Sci. 2019;56:61–73.

    Article  CAS  PubMed  Google Scholar 

  144. Esteva A, Kuprel B, Novoa RA, Ko J, Swetter SM, Blau HM, et al. Dermatologist-level classification of skin cancer with deep neural networks. Nature. 2017;542:115–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Faust K, Xie Q, Han D, Goyle K, Volynskaya Z, Djuric U, et al. Visualizing histopathologic deep learning classification and anomaly detection using nonlinear feature space dimensionality reduction. BMC Bioinforma. 2018;19:173.

    Article  Google Scholar 

  146. Erturk A, Bradke F. High-resolution imaging of entire organs by 3-dimensional imaging of solvent cleared organs (3DISCO). Exp Neurol. 2013;242:57–64.

    Article  PubMed  Google Scholar 

  147. Dodt HU, Leischner U, Schierloh A, Jahrling N, Mauch CP, Deininger K, et al. Ultramicroscopy: three-dimensional visualization of neuronal networks in the whole mouse brain. Nat methods. 2007;4:331–6.

    Article  CAS  PubMed  Google Scholar 

  148. Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, et al. Structural and molecular interrogation of intact biological systems. Nature. 2013;497:332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Yang B, Treweek JB, Kulkarni RP, Deverman BE, Chen CK, Lubeck E, et al. Single-cell phenotyping within transparent intact tissue through whole-body clearing. Cell. 2014;158:945–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Susaki EA, Tainaka K, Perrin D, Kishino F, Tawara T, Watanabe TM, et al. Whole-brain imaging with single-cell resolution using chemical cocktails and computational analysis. Cell. 2014;157:726–39.

    Article  CAS  PubMed  Google Scholar 

  151. Nojima S, Susaki EA, Yoshida K, Takemoto H, Tsujimura N, Iijima S, et al. CUBIC pathology: three-dimensional imaging for pathological diagnosis. Sci Rep. 2017;7:9269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hama H, Hioki H, Namiki K, Hoshida T, Kurokawa H, Ishidate F, et al. ScaleS: an optical clearing palette for biological imaging. Nat Neurosci. 2015;18:1518–29.

    Article  CAS  PubMed  Google Scholar 

  153. Yu T, Qi Y, Gong H, Luo Q, Zhu D Optical clearing for multiscale biological tissues. J Biophotonics. 2018;11: e201700187.

Download references

Acknowledgements

J.K. is supported by CIHR CGSM studentship. Research time and space for P.D. is provided by the Princess Margaret Cancer Centre and University Health Network Department of Pathology.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Karl Grenier, Jennifer Kao & Phedias Diamandis

  2. Laboratory Medicine Program, Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada

    Jennifer Kao & Phedias Diamandis

  3. Princess Margaret Cancer Centre, MacFeeters Hamilton Centre for Neuro-Oncology Research, 101 College Street, Toronto, ON, M5G 1L7, Canada

    Phedias Diamandis

Authors
  1. Karl Grenier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Phedias Diamandis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All Authors contributed to the preparation of the manuscript equally.

Corresponding author

Correspondence to Phedias Diamandis.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grenier, K., Kao, J. & Diamandis, P. Three-dimensional modeling of human neurodegeneration: brain organoids coming of age. Mol Psychiatry 25, 254–274 (2020). https://doi.org/10.1038/s41380-019-0500-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0500-7

This article is cited by

Search

Advanced search

Quick links