title: Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid β.
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.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors.forename: Valerie
authors.initials: V
authors.lastname: Vingtdeux
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Institut Cochin, INSERM U1016, Paris 75014, France, CNRS, UMR 8104, Paris 75014, France, and Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, eklann@cns.nyu.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D016564:Amyloid beta-Protein Precursor; D020652:Peptide Elongation Factor 2; D053764:Presenilin-1; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C580804:presenilin 1, mouse; C516138:dorsomorphin; D054736:Elongation Factor 2 Kinase; D055372:AMP-Activated Protein Kinases
keywords: Alzheimer's disease; long-term potentiation; neurodegeneration; protein synthesis; signaling; translation