Abstract
The conventional view of central nervous system (CNS) metabolism is based on the assumption that glucose is the main fuel source for active neurons and is processed in an oxidative manner. However, since the early 1990s research has challenged the idea that the energy needs of nerve cells are met exclusively by glucose and oxidative metabolism. This alternative view of glucose utilization contends that astrocytes metabolize glucose to lactate, which is then released and taken up by nearby neurons and used as a fuel source, commonly known as the astrocyte-neuron lactate shuttle (ANLS) model. Once thought of as a waste metabolite, lactate has emerged as a central player in the maintenance of neuronal function and long-term memory. Decreased neuronal metabolism has traditionally been viewed as a hallmark feature of Alzheimer's disease (AD). However, a more complex picture of CNS metabolism is emerging that may provide valuable insight into the pathophysiological changes that occur during AD and other neurodegenerative diseases. This review will examine the ANLS model and present recent evidence highlighting the critical role that lactate plays in neuronal survival and memory. Moreover, the role of glucose and lactate metabolism in AD will be re-evaluated from the perspective of the ANLS.
Highlights
The human brain consumes approximately 20% of the body’s total energy yet only represents 2% of the total body mass, far outweighing the demand of other organs in the body
Glutamate triggers a cascade of molecular events leading to an enhancement of glucose utilization by astrocytes [16]. These findings led to the formation of the astrocyte-neuron lactate shuttle (ANLS) model (Figure 1), first proposed 18 years ago, which posits that (1) neuronal activity increases extracellular glutamate which is taken up by astrocytes via glutamate transporters leading to (2) a triggering of glucose uptake and aerobic glycolysis in astrocytes which (3) leads to a large increase in the production of lactate followed by its release into the extracellular space and (4) transport into neurons where it is used as an energy substrate for oxidative and nonoxidative derived ATP production
Given that metabolic dysfunction is tightly linked to neurodegenerative diseases, including Alzheimer’s disease (AD), further studies measuring aerobic glycolysis in vivo are warranted
Summary
The human brain consumes approximately 20% of the body’s total energy yet only represents 2% of the total body mass, far outweighing the demand of other organs in the body. Glutamate triggers a cascade of molecular events leading to an enhancement of glucose utilization by astrocytes [16] These findings led to the formation of the astrocyte-neuron lactate shuttle (ANLS) model (Figure 1), first proposed 18 years ago, which posits that (1) neuronal activity increases extracellular glutamate which is taken up by astrocytes via glutamate transporters leading to (2) a triggering of glucose uptake and aerobic glycolysis in astrocytes which (3) leads to a large increase in the production of lactate followed by its release into the extracellular space and (4) transport into neurons where it is used as an energy substrate for oxidative and nonoxidative derived ATP production (for review see [29]). Astrocytes and neurons preferentially use different metabolic pathways which is, in part, due to cell type-specific expression patterns of key genes regulating energy metabolism, as discussed below
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