Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Jee Hyun Yi, Christopher Brown, Garry Whitehead, Thomas Piers, Young Seok Lee, Celia Martinez Perez, Philip Regan, Daniel J. Whitcomb, Kwangwook Cho

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)
236 Downloads (Pure)

Abstract

Abstract Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease.
Original languageEnglish
Pages (from-to)42-51
JournalPharmacological Research
Early online date14 Apr 2017
DOIs
Publication statusE-pub ahead of print - 14 Apr 2017

Keywords

  • Glucocorticoids
  • GSK-3
  • Tau
  • Long-term potentiation

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