Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid β

Tao Ma, Yiran Chen, Valerie Vingtdeux, Haitian Zhao, Benoit Viollet, Philippe Marambaud, Eric Klann

Research output: Contribution to journalArticle

Abstract

The AMP-activated protein kinase (AMPK) is a Ser/Thr kinase that is activated in response to low-energy states to coordinate multiple signaling pathways to maintain cellular energy homeostasis. Dysregulation of AMPK signaling has been observed in Alzheimer's disease (AD), which is associated with abnormal neuronal energy metabolism. In the current study we tested the hypothesis that aberrantAMPK signaling underlies AD-associated synaptic plasticity impairments by using pharmacological and genetic approaches. We found that amyloid β (Aβ)-induced inhibition of long-term potentiation (LTP) and enhancement of long-term depression were corrected by the AMPK inhibitor compound C (CC). Similarly, LTP impairments in APP/PS1 transgenic mice that model AD were improved by CC treatment. In addition, Aβ-induced LTP failure was prevented in mice with genetic deletion of the AMPK α2-subunit, the predominant AMPK catalytic subunit in the brain. Furthermore, we found that eukaryotic elongation factor 2 (eEF2) and its kinase eEF2K are key downstream effectors that mediate the detrimental effects of hyperactive AMPK in AD pathophysiology. Our findings describe a previously unrecognized role of aberrant AMPK signaling in AD-related synaptic pathophysiology and reveal a potential therapeutic target for AD.

Original languageEnglish (US)
Pages (from-to)12230-12238
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number36
DOIs
StatePublished - Sep 3 2014

    Fingerprint

Keywords

  • Alzheimer's disease
  • Long-term potentiation
  • Neurodegeneration
  • Protein synthesis
  • Signaling
  • Translation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this