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. 1. Introduction 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. While other tissues in the body rely on a variety of energy sources, the brain is believed to primarily depend upon the oxidation of glucose to meet its energy demands. The majority of the energy produced by the oxidation of glucose is used for the maintenance and restoration of ion gradients associated with synaptic transmission, as well as uptake and recycling of neurotransmitters [1]. As an essential organ, the brain requires adequate glucose and oxygen delivery from the vasculature system, a process controlled by the precise regulation of energy supply and demand. Consequently, changes in brain activity are accompanied by changes in cerebral blood flow, a phenomenon which forms the basis of functional brain imaging technologies. For decades, glucose has been considered as the main, if not exclusive energy substrate for the adult brain. Glucose is normally metabolized through the glycolytic pathway to pyruvate and, in the presence of oxygen, is fully oxidized to CO2 and water in the mitochondria. Over 17 times more energy is produced from mitochondrial respiration than from glycolysis
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