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 journalArticlepeer-review

26 Citations (SciVal)


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
Number of pages10
JournalPulmonary Pharmacology & Therapeutics
Early online date14 Apr 2017
Publication statusPublished - 1 Jul 2017


  • Animals
  • Glucocorticoids/metabolism
  • Glycogen Synthase Kinase 3/metabolism
  • Hippocampus/physiology
  • Long-Term Potentiation
  • Phosphorylation
  • Rats
  • Signal Transduction
  • Synapses/physiology
  • tau Proteins/metabolism


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