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Tau Mislocation in Glucocorticoid-Triggered Hippocampal Pathology

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Abstract

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.

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Abbreviations

GC:

Glucocorticoids

MT:

Microtubules

AD:

Alzheimer’s disease

MWM:

Morris water maze

PSD-95:

Postsynaptic density protein 95

DEX:

Dexamethasone

GluN2B:

NMDA receptor 2B

GluA2:

AMPA receptor 2

ANOVA:

Analysis of variance

TEM:

Transmission electron microscopy

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Acknowledgments

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).

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None of the authors report competing interests.

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    Authors and Affiliations

    1. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal

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

    2. ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal

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

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    1. Sara Pinheiro
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    Correspondence to Ioannis Sotiropoulos.

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    Sara Pinheiro and Joana Silva contributed equally to this work.

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    Pinheiro, S., Silva, J., Mota, C. et al. Tau Mislocation in Glucocorticoid-Triggered Hippocampal Pathology. Mol Neurobiol 53, 4745–4753 (2016). https://doi.org/10.1007/s12035-015-9356-2

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