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

T Ma, Y Chen, V Vingtdeux, H Zhao… - Journal of …, 2014 - Soc Neuroscience
T Ma, Y Chen, V Vingtdeux, H Zhao, B Viollet, P Marambaud, E Klann
Journal of Neuroscience, 2014Soc Neuroscience
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 …
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.
Soc Neuroscience