Skip to main content
Springer Nature Link
Log in

Neurogenic effects of β-amyloid in the choroid plexus epithelial cells in Alzheimer’s disease

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

β-amyloid (Aβ) can promote neurogenesis, both in vitro and in vivo, by inducing neural progenitor cells to differentiate into neurons. The choroid plexus in Alzheimer’s disease (AD) is burdened with amyloid deposits and hosts neuronal progenitor cells. However, neurogenesis in this brain tissue is not firmly established. To investigate this issue further, we examined the effect of Aβ on the neuronal differentiation of choroid plexus epithelial cells in several experimental models of AD. Here we show that Aβ regulates neurogenesis in vitro in cultured choroid plexus epithelial cells as well as in vivo in the choroid plexus of APP/Ps1 mice. Treatment with oligomeric Aβ increased proliferation and differentiation of neuronal progenitor cells in cultured choroid plexus epithelial cells, but decreased survival of newly born neurons. These Aβ-induced neurogenic effects were also observed in choroid plexus of APP/PS1 mice, and detected also in autopsy tissue from AD patients. Analysis of signaling pathways revealed that pre-treating the choroid plexus epithelial cells with specific inhibitors of TyrK or MAPK diminished Aβ-induced neuronal proliferation. Taken together, our results support a role of Aβ in proliferation and differentiation in the choroid plexus epithelial cells in Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Kitada M, Chakrabortty S, Matsumoto N, Taketomi M, Ide C (2001) Differentiation of choroid plexus ependymal cells into astrocytes after grafting into the pre-lesioned spinal cord in mice. Glia 36:364–374

    Article  PubMed  CAS  Google Scholar 

  2. Li Y, Chen J, Chopp M (2002) Cell proliferation and differentiation from ependymal, subependymal and choroid plexus cells in response to stroke in rats. J Neurol Sci 193:137–146

    Article  PubMed  Google Scholar 

  3. Itokazu Y, Kitada M, Dezawa M, Mizoguchi A, Matsumoto N, Shimizu A, Ide C (2006) Choroid plexus ependymal cells host neural progenitor cells in the rat. Glia 53:32–42

    Article  PubMed  Google Scholar 

  4. Luskin MB (1993) Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11:173–189

    Article  PubMed  CAS  Google Scholar 

  5. Chiasson BJ, Tropepe V, Morshead CM, van der Kooy D (1999) Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci 19:4462–4471

    PubMed  CAS  Google Scholar 

  6. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716

    Article  PubMed  CAS  Google Scholar 

  7. Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:466–470

    Article  PubMed  CAS  Google Scholar 

  8. Stone SS, Teixeira CM, Devito LM, Zaslavsky K, Josselyn SA, Lozano AM, Frankland PW (2011) Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci 31:13469–13484

    Article  PubMed  CAS  Google Scholar 

  9. Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325:210–213

    Article  PubMed  CAS  Google Scholar 

  10. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33:569–579

    Article  PubMed  CAS  Google Scholar 

  11. Winner B, Kohl Z, Gage FH (2011) Neurodegenerative disease and adult neurogenesis. Eur J Neurosci 33:1139–1151

    Article  PubMed  Google Scholar 

  12. Rensink AA, de Waal RM, Kremer B, Verbeek MM (2003) Pathogenesis of cerebral amyloid angiopathy. Brain Res Brain Res Rev 43:207–223

    Article  PubMed  CAS  Google Scholar 

  13. Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061

    Article  PubMed  CAS  Google Scholar 

  14. Dietrich MO, Spuch C, Antequera D, Rodal I, De Yebenes JG, Molina JA, Bermejo F, Carro E (2008) Megalin mediates the transport of leptin across the blood–CSF barrier. Neurobiol Aging 29:902–912

    Article  PubMed  CAS  Google Scholar 

  15. Alvira-Botero X, Carro EM (2010) Clearance of amyloid-beta peptide across the choroid plexus in Alzheimer’s disease. Curr Aging Sci 3:219–229

    Article  PubMed  CAS  Google Scholar 

  16. Carro E, Trejo JL, Gomez-Isla T, Leroith D, Torres-Aleman I (2002) Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 8:1390–1397

    Article  PubMed  CAS  Google Scholar 

  17. Zlokovic BV (2004) Clearing amyloid through the blood–brain barrier. J Neurochem 89:807–811

    Article  PubMed  CAS  Google Scholar 

  18. Antequera D, Vargas T, Ugalde C, Spuch C, Molina JA, Ferrer I, Bermejo-Pareja F, Carro E (2009) Cytoplasmic gelsolin increases mitochondrial activity and reduces Abeta burden in a mouse model of Alzheimer’s disease. Neurobiol Dis 36:42–50

    Article  PubMed  CAS  Google Scholar 

  19. Vargas T, Ugalde C, Spuch C, Antequera D, Moran MJ, Martin MA, Ferrer I, Bermejo-Pareja F, Carro E (2010) Abeta accumulation in choroid plexus is associated with mitochondrial-induced apoptosis. Neurobiol Aging 31:1569–1581

    Article  PubMed  CAS  Google Scholar 

  20. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539

    Article  PubMed  CAS  Google Scholar 

  21. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  PubMed  CAS  Google Scholar 

  22. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875

    Article  PubMed  CAS  Google Scholar 

  23. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106:4012–4017

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  26. Calafiore M, Copani A, Deng W (2012) DNA polymerase-β mediates the neurogenic effect of β-amyloid protein in cultured subventricular zone neurospheres. J Neurosci Res 90:559–567

    Article  PubMed  CAS  Google Scholar 

  27. Antequera D, Portero A, Bolos M, Orive G, Hernández RM, Pedraz JL, Carro E (2012) Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of AβPP/Ps1 mice. J Alzheimers Dis 29:187–200

    PubMed  CAS  Google Scholar 

  28. Pérez-González R, Antequera D, Vargas T, Spuch C, Bolós M, Carro E (2011) Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer’s disease. J Alzheimers Dis 24:17–25

    PubMed  Google Scholar 

  29. Braak H, Braak E (1999) Temporal sequence of Alzheimer’s disease-related pathology. In: Peters A, Morrison JH (eds) Cerebral cortex, vol 14., Neurodegenerative and age-related changes in structure and function of cerebral cortex. Kluwer Academic/Plenum Press, New York, pp 475–512

    Chapter  Google Scholar 

  30. Yu Y, He J, Zhang Y, Luo H, Zhu S, Yang Y, Zhao T, Wu J, Huang Y, Kong J, Tan Q, Li XM (2009) Increased hippocampal neurogenesis in the progressive stage of Alzheimer’s disease phenotype in an APP/Ps1 double transgenic mouse model. Hippocampus 19:1247–1253

    Article  PubMed  Google Scholar 

  31. Esteras N, Bartolomé F, Alquézar C, Antequera D, Muñoz U, Carro E, Martín-Requero A (2012) Altered cell cycle-related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer’s disease [amyloid precursor protein/presenilin 1 (PS1)]. Eur J Neurosci 36:2609–2618

    Article  PubMed  Google Scholar 

  32. Marques F, Sousa JC, Coppola G, Gao F, Puga R, Brentani H, Geschwind DH, Sousa N, Correia-Neves M, Palha JA (2011) Transcriptome signature of the adult mouse choroid plexus. Fluids Barriers CNS 8:1–11

    Article  Google Scholar 

  33. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945

    Article  PubMed  CAS  Google Scholar 

  34. Emerich DF, Skinner SJ, Borlongan CV, Thanos CG (2005) A role of the choroid plexus in transplantation therapy. Cell Transplant 14:715–725

    Article  PubMed  Google Scholar 

  35. Kuhn HG, Palmer TD, Fuchs E (2001) Adult neurogenesis: a compensatory mechanism for neuronal damage. Eur Arch Psychiatry Clin Neurosci 251:152–158

    Article  PubMed  CAS  Google Scholar 

  36. Zhu W, Cheng S, Xu G, Ma M, Zhou Z, Liu D, Liu X (2011) Intranasal nerve growth factor enhances striatal neurogenesis in adult rats with focal cerebral ischemia. Drug Deliv 18:338–343

    Article  PubMed  CAS  Google Scholar 

  37. Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375

    Article  PubMed  CAS  Google Scholar 

  38. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950

    Article  PubMed  CAS  Google Scholar 

  39. Burbach GJ, Hellweg R, Haas CA, Del Turco D, Deicke U, Abramowski D, Jucker M, Staufenbiel M, Deller T (2004) Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J Neurosci 24:2421–2430

    Article  PubMed  CAS  Google Scholar 

  40. Tarkowski E, Issa R, Sjögren M, Wallin A, Blennow K, Tarkowski A, Kumar P (2002) Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol Aging 23:237–243

    Article  PubMed  CAS  Google Scholar 

  41. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 101:343–347

    Article  PubMed  CAS  Google Scholar 

  42. Li L, Xu B, Zhu Y, Chen L, Sokabe M, Chen L (2010) DHEA prevents Aβ25-35-impaired survival of newborn neurons in the dentate gyrus through a modulation of PI3K-Akt-mTOR signaling. Neuropharmacology 59:323–333

    Article  PubMed  CAS  Google Scholar 

  43. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimer Dis 7:63–80

    CAS  Google Scholar 

  44. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15:331–337

    Article  PubMed  CAS  Google Scholar 

  45. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C (2010) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 31:224–243

    Article  PubMed  CAS  Google Scholar 

  46. Spuch C, Antequera D, Portero A, Orive G, Hernández RM, Molina JA, Bermejo-Pareja F, Pedraz JL, Carro E (2010) The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease. Biomaterials 31:5608–5618

    Article  PubMed  CAS  Google Scholar 

  47. Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277:32046–32053

    Article  PubMed  CAS  Google Scholar 

  48. Kim HJ, Chae SC, Lee DK, Chromy B, Lee SC, Park YC, Klein WL, Krafft GA, Hong ST (2003) Selective neuronal degeneration induced by soluble oligomeric amyloid beta protein. FASEB J 17:118–120

    PubMed  CAS  Google Scholar 

  49. Zhang C, McNeil E, Dressler L, Siman R (2007) Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer’s disease. Exp Neurol 204:77–87

    Article  PubMed  CAS  Google Scholar 

  50. 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 24:1–14

    Article  PubMed  CAS  Google Scholar 

  51. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  PubMed  CAS  Google Scholar 

  52. Spuch C, Carro E (2011) The p75 neurotrophin receptor localization in blood–CSF barrier: expression in choroid plexus epithelium. BMC Neurosci 12:39

    Article  PubMed  CAS  Google Scholar 

  53. Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40

    Article  PubMed  CAS  Google Scholar 

  54. Rohe M, Carlo AS, Breyhan H, Sporbert A, Militz D, Schmidt V, Wozny C, Harmeier A, Erdmann B, Bales KR, Wolf S, Kempermann G, Paul SM, Schmitz D, Bayer TA, Willnow TE, Andersen OM (2008) Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem 283:14826–14834

    Article  PubMed  CAS  Google Scholar 

  55. Giovannini MG, Scal C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F (2002) Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis 11:257–274

    Article  PubMed  CAS  Google Scholar 

  56. Franciosi S, Ryu JK, Choi HB, Radov L, Kim SU, McLarnon JG (2006) Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia. J Neurosci 26:11652–11664

    Article  PubMed  CAS  Google Scholar 

  57. Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H, Shimohama S, Perry G, Smith MA (2001) Activation of MKK6, an upstream activator of p38, in Alzheimer’s disease. J Neurochem 79:311–318

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Instituto de Salud Carlos III (FIS 09-01636), Fundación Investigación Médica Mutua Madrileña (2008/93; 2010/0004), and CIBERNED (BESAD-P.2010) awarded to E. Carro. F. Wandosell was additionally supported from Direccion General de Ciencia y Tecnologia-DGCYT (SAF2009-12249-C02-01), EU-FP7-2009-CT222887, Fundación Ramón Areces, and CIBERNED (BESAD-P.2010). C. Spuch was supported by programmes from Xunta de Galicia (INCITE2009, and “Isidro Parga Pondal”). We thank Agnieszka Krzyzanowska, PhD, for the careful revision of this manuscript.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Neuroscience Group, Instituto de Investigacion Hospital, 12 de Octubre (i+12), Av. de Córdoba s/n. 28041, Madrid, Spain

    Marta Bolos & Eva Carro

  2. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain

    Marta Bolos, Lara Ordoñez-Gutierrez, Francisco Wandosell, Isidro Ferrer & Eva Carro

  3. Department of Pathology and Neuropathology, Complejo Hospitalario Universitario de Vigo (CHUVI), Hospital of Meixoeiro, Vigo, Spain

    Carlos Spuch

  4. Centro de Biología Molecular “Severo Ochoa”, CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain

    Lara Ordoñez-Gutierrez & Francisco Wandosell

  5. Institut de Neuropatologia, Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona, Spain

    Isidro Ferrer

Authors
  1. Marta Bolos
    View author publications

    Search author on:PubMed Google Scholar

  2. Carlos Spuch
    View author publications

    Search author on:PubMed Google Scholar

  3. Lara Ordoñez-Gutierrez
    View author publications

    Search author on:PubMed Google Scholar

  4. Francisco Wandosell
    View author publications

    Search author on:PubMed Google Scholar

  5. Isidro Ferrer
    View author publications

    Search author on:PubMed Google Scholar

  6. Eva Carro
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Eva Carro.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 123 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bolos, M., Spuch, C., Ordoñez-Gutierrez, L. et al. Neurogenic effects of β-amyloid in the choroid plexus epithelial cells in Alzheimer’s disease. Cell. Mol. Life Sci. 70, 2787–2797 (2013). https://doi.org/10.1007/s00018-013-1300-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1300-x

Keywords

Profiles

  1. Carlos Spuch View author profile