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Aβ42 Peptide Promotes Proliferation and Gliogenesis in Human Neural Stem Cells

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Abstract

Amyloid-β 42 [Aβ1–42 (Aβ42)] is one of the main Aβ peptide isoforms found in amyloid plaques of brains with Alzheimer’s disease (AD). Although Aβ42 is associated with neurotoxicity, it might mediate several normal physiological processes during embryonic brain development and in the adult brain. However, due to the controversy that exists in the field, relatively little is known about its physiological function. In the present work, we have analyzed the effects of different concentrations of monomeric Aβ42 on cell death, proliferation, and cell fate specification of human neural stem cells (hNSCs), specifically the hNS1 cell line, undergoing differentiation. Our results demonstrate that at higher concentrations (1 μM), Aβ42 increases apoptotic cell death and DNA damage, indicating that prolonged exposure of hNS1 cells to higher concentrations of Aβ42 is neurotoxic. However, at lower concentrations, Aβ42 significantly promotes cell proliferation and glial cell specification of hNS1 cells by increasing the pool of proliferating glial precursors, without affecting neuronal differentiation, in a concentration-dependent manner. At the molecular level, these effects could be mediated, at least in part, by GSK3β, whose expression is increased by treatment with Aβ42 and whose inhibition prevents the glial specification induced by Aβ42. Since the cellular and molecular effects are known to appear decades before the first clinical symptoms, these types of studies are important in discovering the underlying pathophysiological processes involved in the development of AD. This knowledge could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.

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References

  1. Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Buoso E, Lanni C, Schettini G, Govoni S, Racchi M (2010) Beta-amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain. Pharmacol Res 62(4):308–317

    Article  CAS  PubMed  Google Scholar 

  3. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1):a006189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Blurton-Jones M, Spencer B, Michael S, Castello NA, Agazaryan AA, Davis JL, Müller FJ, Loring JF et al (2014) Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res Ther 5(2):46

    Article  PubMed  PubMed Central  Google Scholar 

  5. Racchi M, Mazzucchelli M, Porrello E, Lanni C, Govoni S (2004) Acetylcholinesterase inhibitors: novel activities of old molecules. Pharmacol Res 50(4):441–451

    Article  CAS  PubMed  Google Scholar 

  6. Gunther EC, Strittmatter SM (2010) Beta-amyloid oligomers and cellular prion protein in Alzheimer’s disease. J Mol Med 88(4):331–338

    Article  CAS  PubMed  Google Scholar 

  7. Iversen LL, Mortishire-Smith RJ, Pollack SJ, Shearman MS (1995) The toxicity in vitro of beta-amyloid protein. Biochem J 311(Pt 1):1–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356

    Article  CAS  PubMed  Google Scholar 

  9. Sisodia SS, St George-Hyslop PH (2002) Gamma-secretase, notch, Abeta and Alzheimer’s disease: where do the presenilins fit in? Nat Rev Neurosci 3(4):281–290

    Article  CAS  PubMed  Google Scholar 

  10. Mazur-Kolecka B, Golabek A, Nowicki K, Flory M, Frackowiak J (2006) Amyloid-beta impairs development of neuronal progenitor cells by oxidative mechanisms. Neurobiol Aging 27(9):1181–1192

    Article  CAS  PubMed  Google Scholar 

  11. Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, Molinaro G, Pappalardo G et al (2009) Beta-amyloid monomers are neuroprotective. J Neurosci 29(34):10582–10587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pearson HA, Peers C (2016) Physiological roles for amyloid beta peptides. J Physiol 575(Pt 1):5–10

    Google Scholar 

  13. del Cárdenas-Aguayo MC, del Silva-Lucero MC, Cortes-Ortiz M, Jiménez-Ramos B, Gómezn Virgilio L, Ramírez-Rodríguez G, Vera- Arroyo E, Fiorentino-Pérez R et al (2014) Physiological role of amyloid beta in neural cells: the cellular trophic activity, neurochemistry, Dr. Thomas Heinbockel (Ed.). InTech. https://doi.org/10.5772/57398

    Google Scholar 

  14. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250(4978):279–282

    Article  CAS  PubMed  Google Scholar 

  15. Whitson JS, Glabe CG, Shintani E, Abcar A, Cotman CW (1990) Beta-amyloid protein promotes neuritic branching in hippocampal cultures. Neurosci Lett 110(3):319–324

    Article  CAS  PubMed  Google Scholar 

  16. Chasseigneaux S, Allinquant B (2012) Functions of Aβ, sAPPα and sAPPβ: similarities and differences. J Neurochem 120(Supl 1):99–108

    Article  CAS  PubMed  Google Scholar 

  17. Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA (2003) The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci 23(13):5531–5535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T et al (2007) Abeta40 inhibits amyloid deposition in vivo. J Neurosci 27(3):627–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen Y, Dong C (2009) Aβ40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ 16:386–394

    Article  CAS  PubMed  Google Scholar 

  20. Fonseca MB, Solá S, Xavier JM, Dionísio PA, Rodrigues CM (2013) Amyloid β peptides promote autophagy-dependent differentiation of mouse neural stem cells: Aβ-mediated neural differentiation. Mol Neurobiol 48(3):829–840

    Article  CAS  PubMed  Google Scholar 

  21. Itokazu Y, Yu RK (2014) Amyloid β-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and notch signaling. Mol Neurobiol 50(1):186–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heo C, Chang KA, Choi HS, Kim HS, Kim S, Liew H, Kim JA, Yu E et al (2007) Effects of the monomeric, oligomeric, and fibrillar Abeta42 peptides on the proliferation and differentiation of adult neural stem cells from subventricular zone. J Neurochem 102(2):493–500

    Article  CAS  PubMed  Google Scholar 

  23. Lee IS, Jung K, Kim IS, Park KI (2013) Amyloid-β oligomers regulate the properties of human neural stem cells through GSK-3β signaling. Exp Mol Med 45:e60

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. López-Toledano MA, Shelanski ML (2004) Neurogenic effect of β-amyloid peptide in the development of neural stem cells. J Neurosci 24(23):5439–5444

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Martínez-Morales PL, Revilla A, Ocaña I, González C, Sainz P, McGuire D, Liste I (2013) Progress in stem cell therapy for major human neurological disorders. Stem Cell Rev 9(5):685–699

    Article  CAS  Google Scholar 

  26. Lindvall O, Kokaia Z (2010) Stem cells in human neurodegenerative disorders—time for clinical translation? J Clin Invest 120(1):29–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Martínez-Morales PL, Liste I (2012) Stem cells as in vitro model of Parkinson’s disease. Stem Cells Int 2012:980941

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Villa A, Snyder EY, Vescovi A, Martínez-Serrano A (2000) Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS. Exp Neurol 161(1):67–84

    Article  CAS  PubMed  Google Scholar 

  29. Villa A, Navarro-Galve B, Bueno C, Franco S, Blasco MA, Martinez-Serrano A (2004) Long-term molecular and cellular stability of human neural stem cell lines. Exp Cell Res 294(2):559–570

    Article  CAS  PubMed  Google Scholar 

  30. Liste I, García-García E, Martínez-Serrano A (2004) The generation of dopaminergic neurons by human neural stem cells is enhanced by Bcl-XL, both in vitro and in vivo. J Neurosci 24(48):10786–10795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Coronel R, Lachgar M, Bernabeu-Zornoza A, Palmer C, Domínguez-Alvaro M, Revilla A, Ocaña I, Fernández A et al (2018, 2018) Neuronal and glial differentiation of human neural stem cells is by amyloid precursor protein (APP) levels. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1167-9

    Article  PubMed  CAS  Google Scholar 

  32. Liste I, García-García E, Bueno C, Martínez-Serrano A (2007) Bcl-XL modulates the differentiation of immortalized human neural stem cells. Cell Death Differ 14(11):1880–1892

    Article  CAS  PubMed  Google Scholar 

  33. Duque A, Rakic P (2011) Different effects of bromodeoxyuridine and [3H] thymidine incorporation into DNA on cell proliferation, position, and fate. J Neurosci 31(42):15205–15217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  35. Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2):99–104

    Article  CAS  PubMed  Google Scholar 

  36. Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) Beta-amyloid (1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28(15):3941–3946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu X, Mei M, Lee HG, Wang Y, Han J, Perry G, Smith MA (2005) P38 activation mediates amyloid-b cytotoxicity. Neurochem Res 30(6–7):791–796

    Article  CAS  PubMed  Google Scholar 

  38. Rogakou EP, Nieves-Neira W, Boon C, Pommier Y, Bonner WM (2000) Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. J Biol Chem 275(13):9390–9395

    Article  CAS  PubMed  Google Scholar 

  39. Bullwinkel J, Baron-Lühr B, Lüdemann A, Wohlenberg C, Gerdes J, Scholzen T (2006) Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol 206(3):624–635

    Article  CAS  PubMed  Google Scholar 

  40. Lehner B, Sandner B, Marschallinger J, Lehner C, Furtner T, Couillard-Despres S, Rivera FJ, Brockhoff G et al (2011) The dark side of BrdU in neural stem cell biology: detrimental effects on cell cycle, differentiation and survival. Cell Tissue Res 345(3):313–328

    Article  CAS  PubMed  Google Scholar 

  41. Boekhoorn K, Joels M, Lucassen PJ (2006) Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis 24(1):1–14

    Article  CAS  PubMed  Google Scholar 

  42. Kirouac L, Rajic AJ, Cribbs DH, Padmanabhan J (2017) Activation of Ras-ERK signaling and GSK-3 by amyloid precursor protein and amyloid beta facilitates neurodegeneration in Alzheimer’s disease. eNeuro 4(2). https://doi.org/10.1523/ENEURO.0149-16.2017

    Article  PubMed  PubMed Central  Google Scholar 

  43. Trazzi S, Fuchs C, De Franceschi M, Mitrugno VM, Bartesaghi R, Ciani E (2014) APP-dependent alteration of GSK3β activity impairs neurogenesis in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 67:24–36

    Article  CAS  PubMed  Google Scholar 

  44. Fryer JD, Holtzman DM (2005) The bad seed in Alzheimer’s disease. Neuron 47(2):167–168

    Article  CAS  PubMed  Google Scholar 

  45. Zou K, Kim D, Kakio A, Byun K, Gong JS, Kim J, Kim M, Sawamura N et al (2003) Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain. J Neurochem 87(3):609–619

    Article  CAS  PubMed  Google Scholar 

  46. Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298

    Article  CAS  PubMed  Google Scholar 

  47. Müller UC, Deller T, Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18(5):281–298

    Article  PubMed  CAS  Google Scholar 

  48. Lie DC, Song H, Colamarino SA, Ming GL, Gage FH (2004) Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annu Rev Pharmacol 44:399–421

    Article  CAS  Google Scholar 

  49. Ekonomou A, Savva GM, Brayne C, Forster G, Francis PT, Johnson M, Perry EK, Attems J et al (2015) Stage-specific changes in neurogenic and glial markers in Alzheimer’s disease. Biol Psychiatry 77(8):711–719

    Article  CAS  PubMed  Google Scholar 

  50. Díaz-Moreno M, Hortigüela R, Gonçalves A, García-Carpio I, Manich G, García-Bermúdez E, Moreno-Estellés M, Eguiluz C et al (2013) Aβ increases neural stem cell activity in senescence-accelerated SAMP8 mice. Neurobiol Aging 34(11):2623–2638

    Article  PubMed  CAS  Google Scholar 

  51. Llorens-Martín M, Jurado J, Hernández F, Avila J (2014) GSK-3B, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7:46. https://doi.org/10.3389/fnmol.2014.00046

    Article  CAS  PubMed  Google Scholar 

  52. He P, Shen Y (2009) Interruption of B-catenin signaling reduces neurogenesis in Alzheimer’s disease. J Neurosci 29:6545–6557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stagni F, Giacomini A, Guidi S, Ciani E, Bartesagh R (2015) Timing of therapies for Down syndrome: the sooner, the better. Front Behav Neurosci 9:265

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Malmsten L, Vijayaraghvan S, Hovatta O, Marutle A, Darreh-Shori T (2014) Fibrillary β-amyloid 1-42 alters cytokine secretion, cholinergic signalling and neuronal differentiation. J Cel Mol Med 9:1874–1888

    Article  CAS  Google Scholar 

  55. Lei P, Ayton S, Bush AI, Adlard PA (2011) GSK-3 in neurodegenerative diseases. Int J Alzheimers Dis 2011:189246

    PubMed  PubMed Central  Google Scholar 

  56. Engmann O, Giese KP (2009) Crosstalk between Cdk5 and GSK3beta: implications for Alzheimer’s disease. Front Mol Neurosci 2:2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Jaeger A, Baake J, Weiss DG, Kriehuber R (2013) Glycogen synthase kinase-3beta regulates differentiation-induced apoptosis of human neural progenitor cells. Int J Dev Neurosci 31(1):61–68

    Article  CAS  PubMed  Google Scholar 

  58. Kim JS, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS, Son H (2004) Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo. J Neurochem 89(2):324–336

    Article  CAS  PubMed  Google Scholar 

  59. Fuster-Matanzo A, Llorens-Martín M, Sirerol-Piquer MS, García-Verdugo JM, Avila J, Hernández F (2013) Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis. Hum Mol Genet 22(7):1300–1315

    Article  CAS  PubMed  Google Scholar 

  60. Wang H (2018) Modeling neurological diseases with human brain organoids. Front Synaptic Neurosci 10:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Javier Hernández and Cristina Gil for their technical assistance.

Funding

This work was supported by grants from the MICINN-ISCIII (PI-10/00291 and MPY1412/09), MINECO (SAF2015-71140-R) and Comunidad de Madrid (NEUROSTEMCM consortium; S2010/BMD-2336).

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Authors and Affiliations

  1. Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)-CROSADIS, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220, Madrid, Spain

    A. Bernabeu-Zornoza, R. Coronel, C. Palmer, Alberto Zambrano & Isabel Liste

  2. Chronic Disease Programme (UFIEC)-CROSADIS, CIBERNED and CIEN Foundation, Instituto de Salud Carlos III, Madrid, Spain

    M. Calero

  3. Centro de Biología Molecular Severo Ochoa-UAM-CSIC, C/ Nicolás Cabrera 1 UAM-Campus Cantoblanco, Madrid, Spain

    A. Martínez-Serrano

  4. Unidad de Neuro-inflamación, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)-CROSADIS, Instituto de Salud Carlos III, Madrid, Spain

    E. Cano

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  1. A. Bernabeu-Zornoza
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  2. R. Coronel
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  3. C. Palmer
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  4. M. Calero
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  5. A. Martínez-Serrano
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  6. E. Cano
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  7. Alberto Zambrano
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Correspondence to Alberto Zambrano or Isabel Liste.

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Fig. S1

Schematic representation of the experiments and WB analysis. (A) Schematic view of hNS1 differentiation protocol (See Materials and Methods). (B) Exemplary western blot analysis of Aβ42 forms (using 4G8 antibody) present in extracellular medium before Aβ42 treatment. (GIF 332 kb)

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Bernabeu-Zornoza, A., Coronel, R., Palmer, C. et al. Aβ42 Peptide Promotes Proliferation and Gliogenesis in Human Neural Stem Cells. Mol Neurobiol 56, 4023–4036 (2019). https://doi.org/10.1007/s12035-018-1355-7

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