Modeling Alzheimer's Disease Using Human Brain Organoids.

Karina Karmirian, Mariana Holubiec, Livia Goto-Silva, Ivan Fernandez Bessone, Gabriela Vitória, Beatriz Mello, Matias Alloatti, Bart Vanderborght, Tomás L Falzone, Stevens Rehen
Author Information
  1. Karina Karmirian: D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
  2. Mariana Holubiec: Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  3. Livia Goto-Silva: D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
  4. Ivan Fernandez Bessone: Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  5. Gabriela Vitória: D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
  6. Beatriz Mello: D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
  7. Matias Alloatti: Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  8. Bart Vanderborght: D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
  9. Tomás L Falzone: Instituto de Biología Celular y Neurociencia IBCN (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  10. Stevens Rehen: D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil. stevens.rehen@idor.org.

Abstract

Alzheimer's disease (AD) is the primary cause of dementia, to date. The urgent need to understand the biological and biochemical processes related to this condition, as well as the demand for reliable in vitro models for drug screening, has led to the development of novel techniques, among which stem cell methods are of utmost relevance for AD research, particularly the development of human brain organoids. Brain organoids are three-dimensional cellular aggregates derived from induced pluripotent stem cells (iPSCs) that recreate different neural cell interactions and tissue characteristics in culture. Here, we describe the protocol for the generation of brain organoids derived from AD patients and for the analysis of AD-derived pathology. AD organoids can recapitulate beta-amyloid and tau pathological features, making them a promising model for studying the molecular mechanisms underlying disease and for in vitro drug testing.

Keywords

References

  1. Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6(4):487–498. https://doi.org/10.1016/0896-6273(91)90052-2 [DOI: 10.1016/0896-6273(91)90052-2]
  2. Schellenberg GD, Montine TJ (2012) The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 124:305–323. https://doi.org/10.1007/s00401-012-0996-2 [DOI: 10.1007/s00401-012-0996-2]
  3. Zhang Y, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3. https://doi.org/10.1186/1756-6606-4-3 [DOI: 10.1186/1756-6606-4-3]
  4. Kakuda N (2017) Distinct deposition of amyloid-β species in brains with Alzheimer’s disease pathology visualized with MALDI imaging mass spectrometry. Acta Neuropathol Commun 5:1–8 [DOI: 10.1186/s40478-017-0477-x]
  5. Lewczuk P, Lelental N, Spitzer P et al (2014) Amyloid-β 42/40 cerebrospinal fluid concentration ratio in the diagnostics of Alzheimer’s disease: validation of two novel assays. JAD 43:183–191. https://doi.org/10.3233/JAD-140771 [DOI: 10.3233/JAD-140771]
  6. Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179:312–339. https://doi.org/10.1016/j.cell.2019.09.001 [DOI: 10.1016/j.cell.2019.09.001]
  7. Johnson GVW (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117:5721–5729. https://doi.org/10.1242/jcs.01558 [DOI: 10.1242/jcs.01558]
  8. Noble W, Hanger DP, Miller CCJ, Lovestone S (2013) The importance of Tau phosphorylation for neurodegenerative diseases. Front Neurol 4. https://doi.org/10.3389/fneur.2013.00083
  9. Götz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544. https://doi.org/10.1038/nrn2420 [DOI: 10.1038/nrn2420]
  10. Duyckaerts C, Potier M-C, Delatour B (2007) Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115:5–38. https://doi.org/10.1007/s00401-007-0312-8 [DOI: 10.1007/s00401-007-0312-8]
  11. Hall AM, Roberson ED (2012) Mouse models of Alzheimer’s disease. Brain Res Bull 88:3–12. https://doi.org/10.1016/j.brainresbull.2011.11.017 [DOI: 10.1016/j.brainresbull.2011.11.017]
  12. Kitazawa M, Medeiros R, M LaFerla F (2012) Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. CPD 18:1131–1147. https://doi.org/10.2174/138161212799315786 [DOI: 10.2174/138161212799315786]
  13. Sasaguri H, Nilsson P, Hashimoto S et al (2017) APP mouse models for Alzheimer’s disease preclinical studies. EMBO J 36(17):2473–2487. https://doi.org/10.15252/embj.201797397 [DOI: 10.15252/embj.201797397]
  14. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019 [DOI: 10.1016/j.cell.2007.11.019]
  15. Essayan-Perez S, Zhou B, Nabet AM et al (2019) Modeling Alzheimer’s disease with human iPS cells: advancements, lessons, and applications. Neurobiol Dis 130:104503. https://doi.org/10.1016/j.nbd.2019.104503 [DOI: 10.1016/j.nbd.2019.104503]
  16. Zhang W, Jiao B, Zhou M et al (2016) Modeling Alzheimer’s disease with induced pluripotent stem cells: current challenges and future concerns. Stem Cells Int 2016:1–12. https://doi.org/10.1155/2016/7828049 [DOI: 10.1155/2016/7828049]
  17. Oksanen M, Hyötyläinen I, Voutilainen J et al (2018) Generation of a human induced pluripotent stem cell line (LL008 1.4) from a familial Alzheimer’s disease patient carrying a double KM670/671NL (Swedish) mutation in APP gene. Stem Cell Res 31:181–185. https://doi.org/10.1016/j.scr.2018.07.024 [DOI: 10.1016/j.scr.2018.07.024]
  18. Li Y, Park C, Vellón L, Li X (2016) iPSCs: from bench to clinical bed. Stem Cells Int 2016:1–2. https://doi.org/10.1155/2016/8367587 [DOI: 10.1155/2016/8367587]
  19. Yin J, VanDongen AM (2021) Enhanced neuronal activity and asynchronous calcium transients revealed in a 3D organoid model of Alzheimer’s disease. ACS Biomater Sci Eng 7(1):254–264. https://doi.org/10.1021/acsbiomaterials.0c01583 [DOI: 10.1021/acsbiomaterials.0c01583]
  20. Raja WK, Mungenast AE, Lin Y-T et al (2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS One 11:e0161969. https://doi.org/10.1371/journal.pone.0161969 [DOI: 10.1371/journal.pone.0161969]
  21. Yagi T, Ito D, Okada Y et al (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20:4530–4539. https://doi.org/10.1093/hmg/ddr394 [DOI: 10.1093/hmg/ddr394]
  22. Chang K-H, Lee-Chen G-J, Huang C-C et al (2019) Modeling Alzheimer’s disease by induced pluripotent stem cells carrying APP D678H mutation. Mol Neurobiol 56:3972–3983. https://doi.org/10.1007/s12035-018-1336-x [DOI: 10.1007/s12035-018-1336-x]
  23. Gerakis Y, Hetz C (2019) Brain organoids: a next step for humanized Alzheimer’s disease models? Mol Psychiatry 24:474–478. https://doi.org/10.1038/s41380-018-0343-7 [DOI: 10.1038/s41380-018-0343-7]
  24. 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(7467):373–379. https://doi.org/10.1038/nature12517 [DOI: 10.1038/nature12517]
  25. Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, Sasai Y (2013) Selforganization of axial polarity inside-out layer pattern and species-specific progenitor dynamics in human ES cell–derived neocortex. Proc Natl Acad Sci 110(50):20284–20289.
  26. Di Lullo E, Kriegstein AR (2017) The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci 18:573–584. https://doi.org/10.1038/nrn.2017.107 [DOI: 10.1038/nrn.2017.107]
  27. Fernandez I, Navarro BJ, Martinez E, Karmirian K, Holubiec M, Alloatti M, Goto-Silva L, Arnaiz Yepez C, Martins-de-Souza D, Nascimento JM, Bruno L, Saez TM, Rehen SK, Falzone TL (2022) DYRK1A regulates the bidirectional axonal transport of APP in human-derived neurons. J Neurosci JN-RM-2551-21-jneuro; JNEUROSCI. 2551-21.2022v1. https://doi.org/10.1523/JNEUROSCI.2551-21.2022
  28. Amin ND, Paşca SP (2018) Building models of brain disorders with three-dimensional organoids. Neuron 100:389–405. https://doi.org/10.1016/j.neuron.2018.10.007 [DOI: 10.1016/j.neuron.2018.10.007]
  29. Paca SP (2018) The rise of three-dimensional human brain cultures. Nature 553:437–445. https://doi.org/10.1038/nature25032 [DOI: 10.1038/nature25032]
  30. Gordon A, Yoon S-J, Tran SS et al (2021) Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat Neurosci. https://doi.org/10.1038/s41593-021-00802-y
  31. Gonzalez C, Armijo E, Bravo-Alegria J et al (2018) Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23:2363–2374. https://doi.org/10.1038/s41380-018-0229-8 [DOI: 10.1038/s41380-018-0229-8]
  32. Haass C, Lemere CA, Capell A et al (1995) The Swedish mutation causes early-onset Alzheimer’s disease by beta-secretase cleavage within the secretory pathway. Nat Med 1(12):1291–1296. https://doi.org/10.1038/nm1295-1291 [DOI: 10.1038/nm1295-1291]
  33. Tanaka Y, Cakir B, Xiang Y, Sullivan GJ, Park IH (2020) Synthetic analyses of single-cell transcriptomes from multiple brain organoids and fetal brain. Cell Rep 30(6):682–1689. https://doi.org/10.1016/j.celrep.2020.01.038 [DOI: 10.1016/j.celrep.2020.01.038]

MeSH Term

Humans
Organoids
Alzheimer Disease
Brain
Amyloid beta-Peptides
Induced Pluripotent Stem Cells

Chemicals

Amyloid beta-Peptides

Word Cloud

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