Scientists, led by a team at Cincinnati Children’s Hospital Medical Center, discovered that the loss of an important energy regulator called AMPK in astrocytes causes neuronal death in laboratory rodents. They also discovered that AMPK loss in neural stem cells or neurons causes spontaneous brain seizures in the animals.
Their findings, “AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival,” were recently published in Cell Reports and led by cancer biologist Biplab Dasgupta, PhD.
“The contribution of astrocytic lactate to neuronal bioenergetics and the mechanisms of astrocytic lactate production are incompletely understood. Through in vivo magnetic resonance spectroscopy, glucose mass spectroscopy, and electroencephalographic and molecular studies, here we show that the energy sensor AMP activated protein kinase (AMPK) regulates neuronal survival in a non-cell-autonomous manner,” noted the researchers.
AMPK is an important energy sensor located in cells throughout the human body. As a cellular energy sensor responding to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies, including fatty acid oxidation, and autophagy. Due to its role as a central regulator of both lipid and glucose metabolism, AMPK is considered to be a potential therapeutic target for the treatment of type 2 diabetes, obesity, and cancer.
In the brain, AMPK is involved in coordinating context-specific metabolic responses in many tissues. AMPK plays roles in both physiological and pathophysiological states. It is highly activated to restore neuronal energy balance, but its over-activation may be deleterious.
Dasgupta explained that deleting AMPK from astrocyte brain cells led to severe disruption of glucose and lactate metabolism in neurons. The clue was discovered from the first ever magnetic resonance spectroscopy studies in brain-specific AMPK deletion mice done at the University of Minnesota (UM).
The collaborative study included Raghavendra Rao, MD, professor, department of pediatrics, and Ivan Tkáč, PhD, assistant professor, department of radiology, both at the University of Minnesota. They revealed that AMPK deleted mice have about 40% lower lactate levels, a key result that was verified in cultured astrocytes.
The laboratory of Christian Gross, PhD, at Cincinnati Children’s Hospital, made the discovery that AMPK deleted neurons demonstrate spontaneous seizures and are vulnerable to low dose seizure-inducing agents and appear to suggest that the popular antidiabetic drug metformin (that also activates AMPK) may mitigate epileptic seizures.
“Very little is known about how astrocytes regulate glycolysis to generate lactate and supply it to neurons to support their metabolism and proper functioning,” Dasgupta noted. “We show for the first time that AMP kinase (AMPK) is the bottom line of the mechanism that controls astrocytic glycolysis and lactate production in the brain. And we show that interfering with this process does little harm to astrocytes but damages neurons.”
The results in mouse brains from the Dasgupta lab were carried out in the brains of the fruit fly Drosophila using six different models of AMPK deletion. Stefanie Schirmeier, PhD, at the University of Münster in Germany, found that AMPK deletion in the fly glia causes neuronal death and reduces lifespan of the mutant flies.
Their findings may lead to a possible treatment for epileptic seizures and highlight the importance of AMPK in lactate production in astrocytes and the role of astrocyte-derived lactate in providing metabolic support for neurons.