Molecular Neurobiology

, Volume 51, Issue 3, pp 1206–1220 | Cite as

Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution

  • C. Vergara
  • L. Ordóñez-Gutiérrez
  • F. Wandosell
  • I. Ferrer
  • J. A. del Río
  • R. Gavín
Article

Abstract

Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic β-amyloid peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. Aβ oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrPC) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the toxic effects of Aβ are upstream of change in tau, a neuronal microtubule-associated protein that promotes the polymerization and stabilization of microtubules. However, tau is considered decisive for the progression of neurodegeneration, and, indeed, tau pathology correlates well with clinical symptoms such as dementia. Different pathways can lead to abnormal phosphorylation, and, as a consequence, tau aggregates into paired helical filaments (PHF) and later on into NFTs. Reported data suggest a regulatory tendency of PrPC expression in the development of AD, and a putative relationship between PrPC and tau processing is emerging. However, the role of tau/PrPC interaction in AD is poorly understood. In this study, we show increased susceptibility to Aβ-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrPC knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrPC expression that paralleled with tau at early ages in an AD murine model and in early Braak stages of AD in affected individuals. Taken together, these results suggest a protective role for PrPC in AD by downregulating tau expression, and they point to this protein as being crucial in the molecular events that lead to neurodegeneration in AD.

Keywords

Alzheimer’s disease Microtubule-associated protein tau Cellular prion protein Aβ oligomers 

Notes

Acknowledgments

This research was supported by BESAD-P, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, for the laboratories of IF, JADR and FW. In addition, work in the laboratory of JADR was supported by grants from FP7-PRIORITY and DEMTEST (Joint Programming of Neurodegenerative Diseases, PI11/03028), Ministerio de Economía y Competitividad (MINECO) (BFU2012-32617), Generalitat de Catalunya (SGR2009-366 and SGR2014-1218), and Obra Social “La Caixa”. RG was supported by Fondo de Investigaciones Sanitarias (PI11-00075) and work in FW’s lab was supported by grants from the Direccion General de Ciencia y Tecnologia (DGCYT) (SAF2012-39148-C03-01), and EU-FP7-2009-(CT222887), as well as an institutional grant from the ‘Fundación Areces”. CV is supported by the Ministerio de Ciencia e Innovación (MICINN). The authors declare that they have no competing interests. We thank T. Yohannan for editorial assistance and M. Segura for technical assistance.

Supplementary material

12035_2014_8793_Fig6_ESM.jpg (400 kb)
Supplementary Fig. 1

a Electrophoretic characterization of different Aβ1-42 amyloid species. Peptide was matured under protocols for ADDLs or fibril formation prior to peptide culture treatments. Immunoblot was done with 6E10 monoclonal antibody. b, c TEM analysis of Aβ1-42 24 hours post-dissolution under oligomer- (b) or fibril-forming conditions (c). Scale bar: 200 nm. d Western blot analysis of total tau level or phosphorylated tau level (epitopes ser396/404, ser202/thr205, and thr181, respectively) in cortical cultures from Prnp 0/0, PrnP +/+ , and Tg20 mouse samples (n = 6, Prnp 0/0; n = 6 PrnP +/+ and n = 6 Tg20) after 24 hours of ADDL treatment. (JPEG 400 kb)

12035_2014_8793_Fig7_ESM.jpg (56 kb)
Supplementary Fig. 2

Comparative analysis of cortical primary culture from Prnp 0/0 mice treated with ADDLs or fibrillar Aβ1-42, respectively, for 6 hours (n = 3 ADDLs and n = 4 Aβ1-42). Note that tau expression increases only when cells are treated with oligomers. (JPEG 56 kb)

12035_2014_8793_Fig8_ESM.jpg (159 kb)
Supplementary Fig. 3

Characterization of the APP/PS1 mouse model used in this study. a-d Immunohistochemical analysis of 9-month-old animals with 4G8 monoclonal antibody for detection of amyloid plaques. Scale bars a, b, c = 200 μm Scale bar d = 40 μm. Abbreviations including H, hilus; GCL, granular cell layer; ML, molecular layer; SLM, stratum lacunosum-moleculare; SR, stratum radiatum; SP, stratum pyramidale; SO, stratum oriens; WM, white matter and I–VIb, neocortical layers. a Absence of amyloid plaques in brain sections of wild-type mice in contrast to Aβ deposits found in transgenic mice (b, c). d Higher magnification of the immunolabeled plaque framed in c. e Increasing levels of soluble Aβ1-42 amyloid with age quantified by ELISA. 9 animals were analyzed for each age. (JPEG 158 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • C. Vergara
    • 1
    • 2
  • L. Ordóñez-Gutiérrez
    • 2
    • 4
  • F. Wandosell
    • 2
    • 4
  • I. Ferrer
    • 2
    • 5
  • J. A. del Río
    • 1
    • 2
    • 3
  • R. Gavín
    • 1
    • 2
    • 3
  1. 1.Molecular and Cellular NeurobiotechnologyInstitute for Bioengineering of CataloniaBarcelonaSpain
  2. 2.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
  3. 3.Department of Cell Biology, Faculty of BiologyUniversity of BarcelonaBarcelonaSpain
  4. 4.Centro de Biología Molecular Severo Ochoa, Cabrera 1, CBM-UAMMadridSpain
  5. 5.Institute of Neuropathology, IDIBELL-Hospital Universitari de Bellvitge, Faculty of MedicineUniversity of BarcelonaHospitalet de LlobregatSpain

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