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Aβ42 Peptide Promotes Proliferation and Gliogenesis in Human Neural Stem Cells

  • A. Bernabeu-Zornoza
  • R. Coronel
  • C. Palmer
  • M. Calero
  • A. Martínez-Serrano
  • E. Cano
  • Alberto Zambrano
  • Isabel Liste
Article

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.

Keywords

Aβ42 peptide Human neural stem cells Alzheimer’s disease Cell death Cell fate specification Cell proliferation 

Notes

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).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1355_Fig8_ESM.gif (333 kb)
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)
12035_2018_1355_MOESM1_ESM.tif (48.2 mb)
High Resolution (TIF 49385 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)-CROSADISInstituto de Salud Carlos III (ISCIII)MadridSpain
  2. 2.Chronic Disease Programme (UFIEC)-CROSADIS, CIBERNED and CIEN FoundationInstituto de Salud Carlos IIIMadridSpain
  3. 3.Centro de Biología Molecular Severo Ochoa-UAM-CSICMadridSpain
  4. 4.Unidad de Neuro-inflamación, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)-CROSADISInstituto de Salud Carlos IIIMadridSpain

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