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Journal ArticleDOI

The role of myelin and oligodendrocytes in axonal energy metabolism.

01 Dec 2013-Current Opinion in Neurobiology (Curr Opin Neurobiol)-Vol. 23, Iss: 6, pp 1065-1072
TL;DR: Studying axo-glial signalling and energy metabolism will lead to a better understanding of neurodegenerative diseases, in which axonal energy metabolism fails, including neurological disorders as diverse as multiple sclerosis, leukodystrophies, and amyotrophic lateral sclerosis.
About: This article is published in Current Opinion in Neurobiology.The article was published on 2013-12-01. It has received 260 citations till now. The article focuses on the topics: Myelin.
Citations
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Journal ArticleDOI
20 May 2015-Neuron
TL;DR: This article aims at providing an integration of brain energy metabolism across resolution scales with decisive insights into the understanding of the cellular and molecular bases of the coupling between neuronal activity and energy metabolism.

806 citations


Cites background from "The role of myelin and oligodendroc..."

  • ...A similar intercellular trafficking of lactate across gap junctions necessary for axonal function has been shown to occur between astrocytes and oligodendrocytes (Fünfschilling et al., 2012; Saab et al., 2013)....

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Journal ArticleDOI
TL;DR: Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.
Abstract: Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.

595 citations

Journal ArticleDOI
22 Oct 2014-Neuron
TL;DR: An overview of axonal transport pathways is provided and their role in neuronal function is discussed and Retrograde transport, which plays a major role in neurotrophic and injury response signaling, is discussed.

538 citations


Cites background from "The role of myelin and oligodendroc..."

  • ...However, it remains unclear whether on-board energy production by Neuron 84, October 22, 2014 ª2014 Elsevier Inc. 301 glycolysis is required for axonal transport in vivo, as the energetic lives of glia and neurons are intimately linked (Saab et al., 2013)....

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Journal ArticleDOI
22 Mar 2017-Neuron
TL;DR: The structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults are presented and the pathways that contribute to peripheral nerve injury in DN are discussed.

520 citations


Cites background from "The role of myelin and oligodendroc..."

  • ...Here, in addition to their well-known role in saltatory conduction, oligodendrocytes serve as a source of energy-rich metabolites (lactate) for the axonal compartment, thereby supporting axonal ATP production and energy homeostasis (Beirowski, 2013; Saab et al., 2013)....

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Journal ArticleDOI
TL;DR: The current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons are summarized.
Abstract: Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons.

483 citations


Cites background from "The role of myelin and oligodendroc..."

  • ...(From Saab et al. 2013; modified, with permission, from Elsevier Limited # 2013.)...

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References
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Journal ArticleDOI
TL;DR: Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.
Abstract: Background Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. Methods Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. Results Transected axons were a consistent feature of the lesions of multiple sclerosis...

3,903 citations


"The role of myelin and oligodendroc..." refers background in this paper

  • ...Axonal degeneration in MS has been intensely studied [33,34], but here the causal relationship of inflammation, demyelination, and axon loss has remained unclear [35]....

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Journal ArticleDOI
TL;DR: It is reported that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes and is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
Abstract: 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.

2,521 citations


"The role of myelin and oligodendroc..." refers background in this paper

  • ...The latter, referred to as the ‘lactate shuttle’ [23], has been hypothesized to constantly adjust synaptic glucose utilization and energy consumption to glutamatergic neurotransmission [24,25], which is also important to memory formation [26 ]....

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Journal ArticleDOI
TL;DR: Data that support neurodegeneration as the major cause of irreversible neurological disability in MS patients are reviewed and it is questioned whether inflammatory demyelination is primary or secondary in the disease process.
Abstract: Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. The clinical disease course is variable, usually starts with reversible episodes of neurological disability in the third or fourth decade of life, and transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. We review data that support neurodegeneration as the major cause of irreversible neurological disability in MS patients. We question whether inflammatory demyelination is primary or secondary in the disease process and discuss the challenges of elucidating the cause of MS and developing therapies that will delay or prevent the irreversible and progressive neurological decline that most MS patients endure.

1,560 citations


"The role of myelin and oligodendroc..." refers background in this paper

  • ...Axonal degeneration in MS has been intensely studied [33,34], but here the causal relationship of inflammation, demyelination, and axon loss has remained unclear [35]....

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Journal ArticleDOI
01 Mar 1997-Brain
TL;DR: The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions, which may have implications for the design and timing of therapeutic intervention.
Abstract: One of the histological hallmarks of early multiple sclerosis lesions is primary demyelination, with myelin destruction and relative sparing of axons. On the other hand, it is widely accepted that axonal loss occurs in, and is responsible for, the permanent disability characterizing the later chronic progressive stage of the disease. In this study, we have used an antibody against amyloid precursor protein, known to be a sensitive marker of axonal damage in a number of other contexts, in immunocytochemical experiments on paraffin embedded multiple sclerosis lesions of varying ages in order to see at which stage of the disease axonal damage, in addition to demyelination, occurs and may thus contribute to the development of disability in patients. The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions. This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent disability.

1,532 citations


"The role of myelin and oligodendroc..." refers background in this paper

  • ...Axonal degeneration in MS has been intensely studied [33,34], but here the causal relationship of inflammation, demyelination, and axon loss has remained unclear [35]....

    [...]

Journal ArticleDOI
26 Jul 2012-Nature
TL;DR: It is shown 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.
Abstract: 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.

1,298 citations


"The role of myelin and oligodendroc..." refers background in this paper

  • ...[7 ])....

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  • ...Glycolytic oligodendrocytes support the axonal energy metabolism Two recent papers have shed new light on the role of oligodendrocytes in the adult brain, and have identified at least one axonal support mechanism [6 ,7 ]....

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  • ...It caused a late-onset pathology with axonal spheroids and degeneration in the brain and the spinal cord [7 ], virtually identical to the axonopathy of Plp1 null mutant mice [4] discussed above....

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  • ...Importantly, MCT1 blockage could be rescued by adding free lactate to the medium, demonstrating that neurodegeneration is due to diminished lactate export from oligodendrocytes and not import into neurons [7 ]....

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  • ...As detailed below, oligodendrocytes provide metabolic support to axons, but it is the glial glycolysis products (lactate or pyruvate) that are required for axon function and not glucose itself [6 ,7 ]....

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