Discovery of cellular mechanism to maintain brain’s energy

Astrocytes stained for their cellular markers © Alice Braga
Astrocytes stained for their cellular markers

A key mechanism which detects when the brain needs an additional energy boost to support its activity has been identified in a study in mice and cells.

The scientists say their findings, published in Nature, could inform new therapies to maintain brain health and longevity, as other studies have found that brain energy metabolism can become impaired late in life and contribute to cognitive decline and the development of neurodegenerative disease.

The research was begun by Dr Shefeeq Theparambil, formerly of University College London and now at Lancaster University.

Dr Theparambil said: “The normal activities of the brain require enormous amounts of energy, comparable to that of a human leg muscle running a marathon. This energyis primarily derived from blood glucose. Neurons in the brain consume more than 75% of this energy, and any deficiency in neuronal energy production significantly affects critical brain functions, including learning, memory, and cognition.

“When the brain engages in a specific task, the energy requirements of the involved nerve cells escalate, demanding an increased supply of nutrients. The brain adapts to these increased energy demands by locally boosting the energy supply. This adaptive response ensures that areas of the brain experiencing heightened activity receive additional nutrients.

“However, the brain is a complex organ with diverse cell types, including various non-neuronal glial cells, making it challenging to dissect the precise cellular mechanisms mediating this metabolic adaptation.This study identifies a novel signaling pathway in astrocytes—star-shaped, non-neuronal glial cells in the brain—essential for supporting neurons with energy needs. Astrocytes activate this signalling pathway by sensing neuronal cries for energy, providing the necessary metabolites to boost energy production in neurons.”

Prior research has shown that numerous brain cells called astrocytes appear to play a role in providing the brain neurons with energy they need. Astrocytes, shaped like stars, are a type of glial cell, which are non-neuronal cells found in the central nervous system. When neighbouring neurons need an increase in energy supply, astrocytes jump into action by rapidly activating their own glucose stores and metabolism, leading to the increased production and release of lactate. Lactate supplements the pool of energy that is readily available for use by neurons in the brain.

Co-author Professor Gourine from UCL said: “In our study, we have figured out how exactly astrocytes are able to monitor the energy use by their neighbouring nerve cells, and kick-start this process that delivers additional chemical energy to busy brain regions.”

In a series of experiments using mouse models and cell samples, researchers identified a molecule called 'adenosine' that is released when neurons require more energy. This adenosine is sensed by neighboring astrocytes via a specific set of adenosine receptors, leading to the rapid activation of a signaling pathway in astrocytes. This, in turn, results in the immediate release of metabolic substrates from astrocytes that boost neuronal energy production and preserve their essential functions

The researchers found that the metabolic signalling pathway activated by adenosine in astrocytes is exactly the same as the pathway that recruits energy stores in the muscle and the liver, for example when we exercise.

Adenosine activates astrocyte glucose metabolism and supply of energy to neurons to ensure that synaptic function (neurotransmitters passing communication signals between cells) continues apace under conditions of high energy demand or reduced energy supply.

The researchers found that when they deactivated this key astrocyte adenosine receptorin mice, the animal’s brain activity was less effective, including significant impairments in global brain energy metabolism, memory formation and disruption of sleep, thus demonstrating that the signalling pathway they identified is vital for processes such as learning, memory and sleep.

Dr Theparambil added: “Identification of this mechanism may have broader implications as it could be a way of treating brain diseases where brain energetics are downregulated, such as neurodegeneration and dementia. The results from this study suggest that pharmacological targeting of this pathway could be an attractive and readily druggable target to rescue brain energetics and cognition in brain diseases where low energy metabolism is predominant.”

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