Novel synthetic small‐molecule activators of AMPK as enhancers of autophagy and amyloid‐β peptide degradation

Vingtdeux, Valérie; Chandakkar, Pallavi; Zhao, Haitian; d’Abramo, Cristina; Davies, Peter; Marambaud, Philippe

doi:10.1096/fj.10-167361

Cited by 209 publications

(131 citation statements)

References 62 publications

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“…Previous studies on neurodegenerative disorders showed that the activation of AMPK in different pathological contexts has neuroprotective or deleterious outcomes in various neuronal subtypes (Mairet-Coello et al, 2013;Vingtdeux et al, 2011). The activation of AMPK was reported to increase memory dysfunction in male AβPP mice (DiTacchio et al, 2015).…”

Section: Discussionmentioning

confidence: 97%

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Han

Luo

Sun

et al. 2015

Neuropsychopharmacol

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Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphateactivated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation.

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Section: Discussionmentioning

confidence: 97%

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Han

Luo

Sun

et al. 2015

Neuropsychopharmacol

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“…249 24. Thapsigargin An inhibitor of the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase (SERCA) that inhibits autophagic sequestration through the depletion of intracellular Ca 2+ stores; 250 however, thapsigargin may also block fusion of autophagosomes with endosomes by interfering with recruitment of RAB7, resulting in autophagosome accumulation.…”

Section: Rsvasmentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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“…Several observations demonstrate that AMPK-mediated autophagy has a cytoprotective effect in some models of neurodegenerative disease, such as Huntington's and Alzheimer's diseases, because it contributes to the removal of aggregate-prone mutant proteins and to sustaining neuronal bioenergetics, which is negatively affected under neurodegenerative-associated pro-oxidant conditions (Spencer et al, 2009;Wong and Cuervo, 2010;Underwood et al, 2010;Vingtdeux et al, 2011;Vingtdeux et al, 2010). In support of this assumption, it has been recently suggested that NO-mediated inhibition of autophagy, which is associated with AMPK dephosphorylation, gives rise to a significant increase in huntingtin-containing aggregates in neurons that express the mutant form of the protein (Sarkar et al, 2011).…”

Section: Dual Role Of Ampk In Neurodegenerative Diseasementioning

confidence: 99%

Redox implications of AMPK-mediated signal transduction beyond energetic clues

Cardaci

Filomeni

Ciriolo

2012

Journal of Cell Science

175

154

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SummarySince the discovery of AMP-dependent protein kinase (AMPK), its fundamental role in regulating metabolic pathways and the molecular mechanism underlying the regulation of its activity by adenine nucleotides has been widely studied. AMPK is not only an energy-responsive enzyme, but it also senses redox signals. This review aims at recapitulating the recent lines of evidence that demonstrate the responsiveness of this kinase to metabolic and nitroxidative imbalance, thus providing new insights into the intimate networks of redox-based signals upstream of AMPK. In particular, we discuss its well-recognized activation downstream of mitochondrial dysfunction, debate the recent findings that AMPK is directly targeted by pro-oxidant species, and question alternative redox pathways that allow AMPK to be included into the large class of redox-sensing proteins. The possible therapeutic implications of the role of AMPK in redox-associated pathologies, such as cancer and neurodegeneration, are also discussed in light of recent advances that suggest a role for AMPK in the tuning of redox-dependent processes, such as apoptosis and autophagy.Key words: ROS, Apoptosis, Autophagy, Nitric oxide Introduction Living organisms derive energy from the breakdown of the molecular bonds of nutrients, and then convert it into the more usable forms of ATP and NADPH (see Box 1). Cell homeostasis depends on the maintenance of ATP levels, whose hydrolysis can be coupled to synthesis reactions, transport across membranes and other endoergonic processes. For this reason, cells actively synthesize ATP and have evolved molecular mechanisms aimed at counteracting even slight decreases of ATP (Hardie, 2011). The mutual regulation of the ATP-regenerating and ATP-consuming processes, however, does not depend on the concentration of this single metabolite, but is in response to the energy balance of the cell (Atkinson, 1970). Indeed, the concentration of ATP, which has been estimated to range from 1 to 10 mM, can be subjected to marked variations. Therefore, the absolute intracellular ATP concentration tightly depends on the concentration of the other adenylates (adenylate pool) and should be considered as a function of the adenylate energy charge, which, in accordance

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Novel synthetic small‐molecule activators of AMPK as enhancers of autophagy and amyloid‐β peptide degradation

Cited by 209 publications

References 62 publications

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Guidelines for the use and interpretation of assays for monitoring autophagy

Redox implications of AMPK-mediated signal transduction beyond energetic clues

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