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J Neurosci. 2014 Sep 3;34(36):12230-8. doi: 10.1523/JNEUROSCI.1694-14.2014.

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

Author information

1
Center for Neural Science, New York University, New York, New York 10003.
2
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030.
3
Institut Cochin, INSERM U1016, Paris 75014, France, CNRS, UMR 8104, Paris 75014, France, and Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
4
Center for Neural Science, New York University, New York, New York 10003, eklann@cns.nyu.edu.

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 aberrant AMPK 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.

KEYWORDS:

Alzheimer's disease; long-term potentiation; neurodegeneration; protein synthesis; signaling; translation

PMID:
25186765
PMCID:
PMC4152616
DOI:
10.1523/JNEUROSCI.1694-14.2014
[Indexed for MEDLINE]
Free PMC Article

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