Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/45109

TitleTau mislocation in glucocorticoid-triggered hippocampal pathology
Author(s)Pinheiro, Sara
Silva, Joana
Mota, Cristina de Fátima Sousa da
Silva, João Luís Vaz Lima da
Veloso, Ana Cristina Costa
Pinto, Vítor Manuel Silva
Sousa, Nuno
Cerqueira, João José
Sotiropoulos, I.
KeywordsTau
Glucocorticoids
Synaptic atrophy
Neurodegeneration
Hippocampus
Issue date2016
PublisherHumana Press Inc.
JournalMolecular Neurobiology
CitationPinheiro, S., Silva, J., Mota, C., Vaz-Silva, J., Veloso, A., Pinto, V., . . . Sotiropoulos, I. (2016). Tau Mislocation in Glucocorticoid-Triggered Hippocampal Pathology. [Article]. Molecular Neurobiology, 53(7), 4745-4753. doi: 10.1007/s12035-015-9356-2
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/45109
DOI10.1007/s12035-015-9356-2
ISSN0893-7648
Publisher versionhttp://www.springer.com
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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