Molecular Neurobiology

, Volume 53, Issue 7, pp 4745–4753 | Cite as

Tau Mislocation in Glucocorticoid-Triggered Hippocampal Pathology

  • Sara Pinheiro
  • Joana Silva
  • Cristina Mota
  • João Vaz-Silva
  • Ana Veloso
  • Vítor Pinto
  • Nuno Sousa
  • João Cerqueira
  • Ioannis Sotiropoulos


The exposure to high glucocorticoids (GC) triggers neuronal atrophy and cognitive deficits, but the exact cellular mechanisms underlying the GC-associated dendritic remodeling and spine loss are still poorly understood. Previous studies have implicated sustained GC elevations in neurodegenerative mechanisms through GC-evoked hyperphosphorylation of the cytoskeletal protein Tau while Tau mislocation has recently been proposed as relevant in Alzheimer’s disease (AD) pathology. In light of the dual cytoplasmic and synaptic role of Tau, this study monitored the impact of prolonged GC treatment on Tau intracellular localization and its phosphorylation status in different cellular compartments. We demonstrate, both by biochemical and ultrastructural analysis, that GC administration led to cytosolic and dendritic Tau accumulation in rat hippocampus, and triggered Tau hyperphosphorylation in epitopes related to its malfunction (Ser396/404) and cytoskeletal pathology (e.g., Thr231 and Ser262). In addition, we show, for the first time, that chronic GC administration also increased Tau levels in synaptic compartment; however, at the synapse, there was an increase in phosphorylation of Ser396/404, but a decrease of Thr231. These GC-triggered Tau changes were paralleled by reduced levels of synaptic scaffolding proteins such as PSD-95 and Shank proteins as well as reduced dendritic branching and spine loss. These in vivo findings add to our limited knowledge about the underlying mechanisms of GC-evoked synaptic atrophy and neuronal disconnection implicating Tau missorting in mechanism(s) of synaptic damage, beyond AD pathology.


Tau Glucocorticoids Synaptic atrophy Neurodegeneration Hippocampus 







Alzheimer’s disease


Morris water maze


Postsynaptic density protein 95




NMDA receptor 2B


AMPA receptor 2


Analysis of variance


Transmission electron microscopy



We would like to thank Rui Fernandes for TEM technical support. IS was supported by the Portuguese Foundation for Science and Technology (FCT). This work was funded by the Portuguese Foundation for Science and Technology (FCT) (grant NMC-113934 to IS and grant SFRH/BPD/80118/2011 to JC), Canon Foundation and project DoIT - Desenvolvimento e Operacionalização da Investigação de Translação (N° do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Fatores de Competitividade (POFC).

Conflict of Interest

None of the authors report competing interests.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sara Pinheiro
    • 1
    • 2
  • Joana Silva
    • 1
    • 2
  • Cristina Mota
    • 1
    • 2
  • João Vaz-Silva
    • 1
    • 2
  • Ana Veloso
    • 1
    • 2
  • Vítor Pinto
    • 1
    • 2
  • Nuno Sousa
    • 1
    • 2
  • João Cerqueira
    • 1
    • 2
  • Ioannis Sotiropoulos
    • 1
    • 2
  1. 1.Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of Minho, Campus GualtarBragaPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryBraga/GuimarãesPortugal

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