Oligodendroglia metabolically support axons and contribute to neurodegeneration

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.

Rescue of motoneurons from axotomy-induced cell death by polymer encapsulated cells genetically engineered to release CNTF

Patrick Aebischer

The neurodegenerative disease amyotrophic lateral sclerosis (ALS) results from the progressive loss of motoneurons, leading to death in a few years. Ciliary neurotrophic factor (CNTF), which decreases naturally occurring and axotomy-induced cell death, may result in slowing of motoneuron loss and has been evaluated as a treatment for ALS. Effective administration of this protein to motoneurons may be hampered by the exceedingly short half-life of CNTF, and the inability to deliver effective concentration into the central nervous system after systemic administration in vivo. The constitutive release of CNTF from genetically engineered cells may represent a solution to this delivery problem. In this work, baby hamster kidney (BHK) cells stably tranfected with a chimeric plasmid construct containing the gene for human or mouse CNTF were encapsulated in polymer fibers, which prevents immune rejection and allow long-term survival of the transplanted cells. In vitro bioassays show that the encapsulated transfected cells release bioactive CNTF. In vivo, systemic delivery of human and mouse CNTF from encapsulated cells was observed to rescue 26 and 27% more facial motoneurons, respectively, as compared to capsules containing parent BHK cells 1 wk postaxotomy in neonatal rats. With local application of CNTF on the nerve stump and by systemic delivery through repeated subcutaneous injections, 15 and 13% more rescue effects were observed. These data illustrate the potential of using encapsulated genetically engineered cells to continuously release CNTF to slow down motoneuron degeneration following axotomy and suggest that encapsulated cell delivery of neurotrophic factors may provide a general method for effective administration of therapeutic proteins for the treatment of neurodegenerative diseases.

1996

Feeding active neurons: (re)emergence of a nursing role for astrocytes

Pierre Magistretti, Luc Pellerin

Despite unquestionable evidence that glucose is the major energy substrate for the brain, data collected over several decades with different approaches suggest that lactate may represent a supplementary metabolic substrate for neurons. Starting with the pioneering work of McIlwain in the early 1950s which showed that lactate can sustain the respiratory rate of small brain tissue pieces, this idea receives confirmation with more recent studies using nuclear magnetic resonance spectroscopy undoubtedly demonstrating that lactate is efficiently oxidized by neurons, both in vitro and in vivo. Not only is lactate able to maintain ATP levels and promote neuronal survival but it was also found to support neuronal activity, at least if low levels of glucose are present. Despite the early suggestion for a role of astrocytes in metabolic supply to neurons, it is only recently however that they have been considered as a potential source of lactate for neurons. Moreover, it has been proposed that astrocytes might provide lactate to neurons in response to enhanced synaptic activity by a well-characterized mechanism involving glutamate uptake. The description of specific transporters for lactate on both astrocytes and neurons further suggest that there exist a coordinated mechanism of lactate exchange between the two cell types. Thus it is proposed that astrocytes play a nursing role toward neurons by providing lactate as an additional energy substrate especially during periods of enhanced synaptic activity. The importance of this metabolic cooperation within the central nervous system, although not unique if compared to other organs, still remains to be explored.

2002

Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization

Pierre Magistretti, Luc Pellerin

Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.

1994