Tau Mislocation in Glucocorticoid-Triggered Hippocampal Pathology 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 Received: 10 February 2015 /Accepted: 13 July 2015 /Published online: 2 September 2015 # Springer Science+Business Media New York 2015 Abstract The exposure to high glucocorticoids (GC) trig- gers neuronal atrophy and cognitive deficits, but the exact cellular mechanisms underlying the GC-associated den- dritic remodeling and spine loss are still poorly under- stood. Previous studies have implicated sustained GC ele- vations 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 bio- chemical and ultrastructural analysis, that GC administration led to cytosolic and dendritic Tau accumulation in rat hippo- campus, and triggered Tau hyperphosphorylation in epitopes related to its malfunction (Ser396/404) and cytoskeletal pa- thology (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 mecha- nisms of GC-evoked synaptic atrophy and neuronal discon- nection implicating Tau missorting in mechanism(s) of synap- tic damage, beyond AD pathology. Keywords Tau . Glucocorticoids . Synaptic atrophy . Neurodegeneration . Hippocampus 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 Introduction Stress, largely through the elevation of circulating glucocorti- coids (GCs), impacts on brain structure and function [1–4]. One of the most vulnerable brain areas is the hippocampus, which exhibits remarkable dendritic atrophy and spine loss after GC administration as well as in stress-related pathologies characterized by high GC levels [1, 4]. However, the mecha- nisms underlying these GC-induced deleterious effects that damage hippocampus structural and functional integrity are still poorly understood. Sara Pinheiro and Joana Silva contributed equally to this work. * Ioannis Sotiropoulos ioannis@ecsaude.uminho.pt 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal 2 ICVS/3B’ s - PT Government Associate Laboratory, Braga/ Guimarães, Portugal Mol Neurobiol (2016) 53:4745–4753 DOI 10.1007/s12035-015-9356-2