Metabolic Reprogramming of Astrocytes in Pathological Conditions: Implications for Neurodegenerative Diseases

Abstract

Astrocytes play a pivotal role in maintaining brain energy homeostasis, supporting neuronal function through glycolysis and lipid metabolism. This review explores the metabolic intricacies of astrocytes in both physiological and pathological conditions, highlighting their adaptive plasticity and diverse functions. Under normal conditions, astrocytes modulate synaptic activity, recycle neurotransmitters, and maintain the blood-brain barrier, ensuring a balanced energy supply and protection against oxidative stress. However, in response to central nervous system pathologies such as neurotrauma, stroke, infections, and neurodegenerative diseases like Alzheimer's and Huntington's disease, astrocytes undergo significant morphological, molecular, and metabolic changes. Reactive astrocytes upregulate glycolysis and fatty acid oxidation to meet increased energy demands, which can be protective in acute settings but may exacerbate chronic inflammation and disease progression. This review emphasizes the need for advanced molecular, genetic, and physiological tools to further understand astrocyte heterogeneity and their metabolic reprogramming in disease states.

Keywords: Alzheimer’s disease; Huntington’s disease; L-lactate; astrocyte; fatty acid oxidation; ketone bodies; metabolism; mitochondria; reactive astrocytes.

Figure 1

Glucose metabolism and cholesterol synthesis. Glucose enters the bloodstream and travels to the astrocytes and neurons via GLUT1 and GLUT3 transporters, respectively [64]. In astrocytes, lactate is produced as an end product of glycolysis and is shuttled via monocarboxylate transporters (MCTs) 1 and 4 and taken up by neurons via MCT2. Neurons possess the enzymatic machinery to convert lactate into pyruvate, which is then utilized to fuel the tricarboxylic acid (TCA) cycle. Cholesterol biosynthesis starts with the transport of Acetyl-CoA from the mitochondria to the cytosolic side of the endoplasmic reticulum, where lanosterol is produced. Then, cholesterol will be synthesized via the Bloch pathway, which occurs in the astrocytes, and via the Kandutsch–Russell pathway, which takes place in neurons. The cholesterol produced in the astrocytes is shuttled to neurons in ApoE-containing lipoproteins via ABCA1 transporters and taken up by receptor-mediated endocytosis via LDLR family receptors. Excess cholesterol is metabolized to 24-hydroxycholesterol, which crosses the BBB and passes into circulation to be eliminated through hepatic circulation. Much 24-hydroxycholesterol will be taken up by astrocytes to activate LXR and upregulate the expression levels of ApoE and ABCA1.

Figure 2

The figure contrasts the normal metabolic functions of astrocytes (depicted on the left in green) with the metabolic alterations observed in various sub-states of reactive astrocytes (depicted on the right in light blue). These changes in reactive astrocytes were identified through experimental studies on inflammation and neurodegenerative diseases. It is important to note that the depicted functions do not correspond to a single astrocyte type, and reactive astrocytes may still retain some physiological functions despite their altered states. Figure modified from [128].