Journal
FEBS JOURNAL
Volume 289, Issue 8, Pages 2247-2262Publisher
WILEY
DOI: 10.1111/febs.16151
Keywords
AMP Kinase; astrocyte-neuron lactate shuttle; brain; glucose metabolism; glycolysis; neurodevelopment
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Funding
- National Institutes of Health (NIH) [R01 NS075291, R01 NS099162]
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AMPK is an integrative metabolic sensor that maintains cellular energy balance and plays a crucial role in coordinating intertissue metabolic signaling. Studies suggest a link between AMPK dysregulation and neurodegenerative diseases, although the exact mechanisms involved remain unclear. AMPK activation may have dual effects on neurons, potentially being neuroprotective or pro-apoptotic depending on specific conditions.
The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important role in orchestrating intertissue metabolic signaling. AMPK regulates cell survival, metabolism, and cellular homeostasis basally as well as in response to various metabolic stresses. Studies so far show that the AMPK pathway is associated with neurodegeneration and CNS pathology, but the mechanisms involved remain unclear. AMPK dysregulation has been reported in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neuropathies. AMPK activation appears to be both neuroprotective and pro-apoptotic, possibly dependent upon neural cell types, the nature of insults, and the intensity and duration of AMPK activation. While embryonic brain development in AMPK null mice appears to proceed normally without any overt structural abnormalities, our recent study confirmed the full impact of AMPK loss in the postnatal and aging brain. Our studies revealed that Ampk deletion in neurons increased basal neuronal excitability and reduced latency to seizure upon stimulation. Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in the brain. AMPK's regulation of aerobic glycolysis in astrocytic metabolism warrants further deliberation, particularly glycogen turnover and shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation. In this minireview, we focus on recent advances in AMPK and energy-sensing in the brain.
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