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 ␤ (A␤)-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, A␤-induced LTP failure was prevented in mice with genetic deletion of the AMPK ␣2-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.

Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release

“…cancer (suppression of tumor growth), stroke (neuroprotection), obesity (appetite regulation), and, as recently demonstrated, Alzheimer's disease (Ma et al, 2014). In addition, AMPK inhibition in pancreatic b cells in response to elevated serum glucose is regarded as a requirement for upregulation of insulin secretion (Rutter and Leclerc, 2009).…”

Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

“…LTP is generally considered a form of synaptic plasticity associated with learning and memory formation. In this model, amyloid β causes the activation of AMPK, and this contributes to the observed impair-www.nature.com/aps Liu R et al Acta Pharmacologica Sinica npg ments in plasticity [66] . This raises the obvious question of which protein(s) downstream of AMPK mediate these effects.…”

“…This raises the obvious question of which protein(s) downstream of AMPK mediate these effects. Ma et al [66] showed that eEF2 phosphorylation is elevated in the hippocampus (a brain area crucial for learning) of AD model mice. Most importantly in the present context, the pharmacological inhibition of eEF2K improved the deficit in LTP in the AD mice but not in controls.…”

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway

“…Aβ causes mitochondrial dysfunction in neurons, leading to energy supplement impairment and mitochondria-mediated apoptosis [17,18] . Numerous signaling pathways are involved in Aβ-induced neurotoxicity, including Wnt signal transduction pathways, the PI3K/Akt/ mTOR pathway, the AMP-active protein kinase pathway and the sirtuin pathway [19][20][21][22][23] . DL0410 ((1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(3-(piperidin-1-yl) propan-1-one)dihydrochloride, Figure 1), an acetylcholinesterase/butyrocholinesterase inhibitor, is a new synthetic compound belonging to phthalazinone units, which exhibits a different chemical structure among cholinesterase inhibitors, such as rivastigmine, donepezil, and tacrine.…”