White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis

Abstract

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in β(2) adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

Figure 1

(A) Schematic representation of the astrocyte phosphocreatine (PCr)–creatine (Cr) cycle. Mitochondrial creatine kinase (CK) ensures that adenosine triphosphate (ATP), produced by oxidative phosphorylation, is converted into PCr. Phosphocreatine diffuses to the thin astrocytic processes where it is metabolized to Cr by CK-BB to generate ATP. The expression of CK-BB is stimulated by cAMP (this has been showed in a human astrocytoma cell line and needs confirmation in astrocytes). The propagation of action potentials along axons leads not only to the expulsion of K⁺ but also to rapid vesicular release into the extracellular fluid of glutamate. The most ATP consuming activity in the astrocytic end feet is the Na⁺/K⁺-ATP pump. It takes up K⁺ released by axons after each depolarization, and it establishes the Na⁺ gradient necessary for glutamate uptake by the astrocytic Na⁺-dependent glutamate transporters. (B) In multiple sclerosis (MS), CK-BB levels and activity are reduced by free radicals and/or decreased transcription due to reduced cAMP formation secondary to a loss of astrocytic β₂ adrenergic receptors. As a consequence, PCr is not properly metabolized, leading to failure of the Na⁺/K⁺-ATP pump and reversal of glutamate uptake by the glutamate transporters. Enhanced glutamate levels in the extracellular space surrounding axons may overactivate axonal α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors and lead to glutamate-mediated axonal degeneration. Oligodendrocytes, which express AMPA and N-methyl--aspartate (NMDA) receptors, are also sensitive to excitotoxic damage. EAAT, Excitatory Amino Acid Transporter.

Figure 2

Schematic representation of the possible mechanism underlying N-acetylaspartate (NAA) synthesis by axonal mitochondria. The dashed lines indicate the part of the tricarboxylic acid cycle in neurons that can be bypassed by the conversion of glutamate and oxaloacetate to α-ketoglutarate and aspartate via the enzyme aspartate aminotransferase (AAT). Glutamine is synthetized in astrocytes, released in the extracellular space and taken up by the axons. Acetylation of aspartate by aspartate N-acetyltransferase (asp-N-AT) leads to the formation of NAA, which is removed from neuronal mitochondria, thereby favoring the conversion of glutamate to α-ketoglutarate, which can enter the truncated tricarboxylic acid cycle for adenosine triphosphate (ATP) production.

Figure 3

(A) Schematic representation of the astrocyte-axonal lactate shuttle. Glycogenolysis is mediated by glycogen phosphorylase, which is activated by cAMP-activated protein kinase A in response to neurochemical signals, such as norepinephrine (NE). Glycolysis leads to the formation of lactate, which is taken up by axons via a monocarboxylic acid transporter, and believed to be converted into pyruvate as energy substrate for mitochondrial oxidative metabolism. N-acetylaspartate (NAA) produced by axonal mitochondria is released in the extracellular space and taken up by oligodendrocytes. (B) In multiple sclerosis (MS), white-matter astrocytes are deficient in β₂ adrenergic receptors, resulting in decreased formation of cAMP and subsequently a decrease in glycogenolysis, leading to a decreased production of lactate. This causes a reduction in axonal mitochondrial metabolism as evidenced by a decreased formation of NAA. Reduction in adenosine triphosphate (ATP) supply by mitochondria will lead to failure of the axonal Na⁺/K⁺ pump, resulting in the accumulation of Na⁺ in the axoplasma and stimulation of the Na⁺/Ca²⁺ exchanger to operate in the reverse Ca²⁺ import mode. Together with an overactivation of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors, due to enhanced extracellular glutamate levels, this will increase intraaxonal levels of Ca²⁺, which in turn will lead to an overstimulation of various Ca²⁺-dependent catabolic enzymes and mitochondrial damage. Enhanced levels of nitric oxide (NO) may contribute to mitochondrial dysfunction.

Figure 4

(A) Schematic representation of the astrocyte-axonal glutamine shuttle. Glycogenolysis is mediated by glycogen phosphorylase, which is activated by cAMP-activated protein kinase A in response to neurochemical signals, such as norepinephrine (NE). Glycogen can be degraded via glucose-6-phosphate into pyruvate, which is introduced in the tricarboxylic acid (TCA) cycle. α-Ketoglutarate can leave the TCA cycle to form glutamate that is converted to glutamine by glutamine synthetase. Glutamine is released in the extracellular space, and taken up by the axons to be used in the axonal TCA cycle (see Figure 2). N-acetylaspartate (NAA) produced by axonal mitochondria is released in the extracellular space and taken up by oligodendrocytes. (B) In multiple sclerosis (MS), white-matter astrocytes are deficient in β₂ adrenergic receptors, resulting in decreased glycogenolysis and production of glutamine. This may impair axonal mitochondrial metabolism as evidenced by a decreased formation of NAA, and lead to axonal damage by mechanisms described in Figure 3. AMPA, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid.