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The energetic brain—A review from students to students

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Bordone, Melina Paula, Salman, Mootaz M., Titus, Haley E., Amini, Elham, Andersen, Jens V., Chakraborti, Barnali, Diuba, Artem V., Dubouskaya, Tatsiana G. +28 more·2019·Journal of Neurochemistry
DOI 10.1111/jnc.14829
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Abstract

The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia–neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS . We cover neuronal energy consumption in neural transmission and basic (‘housekeeping’) cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non‐neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS . image

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Written from the paper’s full text.

TL;DR

This narrative review, initiated at the 14th International Society for Neurochemistry Advanced School, synthesizes the basic concepts of brain energy metabolism and explains why the brain has high energy expenditure. It covers neuronal ATP-consuming processes, alternative energy substrates, the role of non-neuronal cells, and how disturbed energy homeostasis contributes to CNS disorders and aging.

Key findings

  • The human brain accounts for 20% of oxygen consumption and 25% of glucose utilization while representing only 2% of body weight (Sokoloff et al. 1977); most adult non-primate vertebrates use 2–8% of total basal metabolism for the CNS (Mink et al. 1981). Herculano-Houzel's analysis concluded that the whole-brain energy budget per neuron is fixed across species, so total glucose use is a linear function of neuron number.
  • After a single action potential, rodent cortical neurons require ~4–8 × 10⁸ ATP molecules to restore Na⁺/K⁺ gradients via the Na⁺/K⁺-ATPase, making AP signaling the second largest metabolic cost after synaptic transmission. Estimates of the AP:postsynaptic-current energy ratio vary from 58:42% (Attwell and Laughlin 2001) to 20:80% (Alle et al. 2009).
  • At a physiological spiking rate of 4 Hz, 15% of total gray-matter ATP maintains resting potential (Attwell and Laughlin 2001); Lennie (2003) attributed 13% of human neocortex energy to spiking, 28% to neuronal resting potential, 10% to glial resting potential, and the remainder to housekeeping. Housekeeping accounts for 25% of gray-matter energy and ~63%/~56% in partially/fully myelinated white matter (Harris and Attwell 2012).
  • Engl et al. (2017) measured O₂ consumption in resting hippocampal slices: it fell 25% after actin cycling blockade, 22% after microtubule turnover blockade, and 18% after lipid and protein metabolism blockade, while blocking protein metabolism alone did not significantly change O₂ consumption.

Methods

  • Narrative review (no primary data collection) initiated at the 14th ISN Advanced School (Varennes Jarcy, France, August 2017), synthesizing published literature on brain energy metabolism.
  • Covers neuronal ATP consumption (presynaptic terminals, postsynaptic terminals, synaptic plasticity, AP generation/propagation, resting potential, housekeeping processes), energy sources (glucose, glutamate, lactate/ANLS, ketone bodies, medium-chain triglycerides), non-neuronal cells (pericytes, astrocytes, oligodendrocytes, microglia), and disease states (aging, T2DM, Alzheimer's, Parkinson's, ALS, MS, TBI/stroke).
  • No systematic search strategy, inclusion criteria, or meta-analysis is described.

Limitations

  • The authors state that brain energetics "can hardly be covered in a single review with satisfying depth" and apologize to scientists not cited "due to space limitations."
  • The text makes evident that several key debates remain unresolved: the ANLS hypothesis is described as "critically viewed and challenged" with contradictory results across experimental settings and "the lack of a consensus-based method for real-time monitoring of metabolic dynamics at cellular resolution"; the proton leak mechanism "remains under debate"; and TBI glucose-transport data are "highly variable requiring further studies."
  • The text notes that the estimated relative contributions of AP generation versus postsynaptic currents to energy expenditure "varied in the literature," and that the estimated cost of axonal transport does not account for tug-of-war events or dynein retrograde transport, so "further modeling is needed."

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/jnc.14829

Cites

331 of 331 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 343 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § Glutamate

    In the absence of glucose, extracellular glutamate was metabolized and mostly converted into aspartate in rat brain homogenate.

    “in the absence of glucose, extracellular glutamate was metabolized and mostly converted into aspartate in rat brain homogenate (Haslam and Krebs, 1963).”
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  • Findingcitation
    § Glutamate

    In vitro experiments in primary cultured neurons indicate that 10 mM of extracellular glutamate causes profound neuronal cell death under normoglycemic and normoxic conditions.

    “In vitro experiments in primary cultured neurons indicate that 10 mM of extracellular glutamate causes profound neuronal cell death under normoglycemic and normoxic conditions (Murphy et al. 1990;Khanna et al. 2003).”
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  • Findingcitation
    § Glutamate

    Oxidation of glutamate in astrocytes as a source of energy is preferred compared to glucose and other substrates.

    “Studies based on substrate competition indicated that oxidation of glutamate in astrocytes as a source of energy is preferred compared to glucose and other substrates (Fig. 2), which suggests the robustness of glutamate use as a substrate for energy in these cells (McKenna et al. 2012).”
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  • Findingcitation
    § Glutamate

    When glucose is removed from media, extracellular glutamate (10 mM) no longer induces cell death.

    “However, when glucose is removed from media, extracellular glutamate (10 mM) no longer induces cell death (Rink et al. 2011).”
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  • Findingcitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Induced alteration in metabolic substrate concentration, through voluntary exercise, has been shown to enhance metabolic enzymes involved in glycolysis, ATP synthesis, ATP transduction, and glutamate turnover.

    “Induced alteration in metabolic substrate concentration, through voluntary exercise, has been shown to enhance metabolic enzymes involved in glycolysis, ATP synthesis, ATP transduction, and glutamate turnover (Ding et al. 2006).”
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    Findingcitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    A clinical study involving administration of sodium lactate reported a three- to fourfold increase in plasma lactate levels along with an average of 17% reduction in the rate of cerebral glucose uptake, indicative of a preferential cerebral uptake of lactate over glucose.

    “Furthermore, a clinical study involving administration of sodium lactate reported a three-to fourfold increase in plasma lactate levels along with an average of 17% reduction in the rate of cerebral glucose uptake, indicative of a preferential cerebral uptake of lactate over glucose (Smith et al. 2003).”
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    Findingnone given
    § Ketone bodies

    Ketone bodies neither alter the plasma membrane potential of presynaptic terminals nor the pH of synaptic vesicles.

    “Additionally, ketone bodies neither alter the plasma membrane potential of presynaptic terminals nor the pH of synaptic vesicles.”
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    Findingcitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Rigorous physical activity increases lactate plasma levels from 0.6 mmol/L to around 2-3 mmol/L, which then crosses the BBB via MCTs.

    “Rigorous physical activity increases lactate plasma levels from 0.6 mmol/L to around 2-3 mmol/ L, which then crosses the BBB via MCTs (Ide et al. 1999).”
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    Findingcitation
    § Ketone bodies

    Inhibition of the MAS and other transaminase reactions on the oxidation of energy substrates increases the oxidation of lactate and β-OHB in astrocytes, but has no significant effect on the rates of β-OHB oxidation and decreases the rate of lactate oxidation by synaptic terminals.

    “Inhibition of the MAS and other transaminase reactions on the oxidation of energy substrates increases the oxidation of lactate and b-OHB in astrocytes, but has no significant effect on the rates of b-OHB oxidation and decreases the rate of lactate oxidation by synaptic terminals (McKenna et al. 1993).”
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    Findingcitation
    § Ketone bodies

    β-OHB supports synaptic vesicle recycling, but reduces both endocytosis and, to a smaller extent, exocytosis.

    “b-OHB supports synaptic vesicle recycling, but reduces both endocytosis and, to a smaller extent, exocytosis (Hrynevich et al. 2016).”
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    Findingcitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Preclinical studies report exercise training in mice augmented the expression of metabolically relevant genes (i.e., peroxisome proliferator-activated receptor gamma coactivator 1alpha, sirtuin-1, and citrate synthase) as well as increased mitochondrial DNA (mtDNA), suggestive of mitochondrial biogenesis in most brain regions studied.

    “Preclinical studies report exercise training in mice augmented the expression of metabolically relevant genes (i.e., peroxisome proliferator-activated receptor gamma coactivator 1alpha, sirtuin-1, and citrate synthase) as well as increased mitochondrial DNA (mtDNA), suggestive of mitochondrial biogenesis in most brain regions studied (Steiner et al. 2011).”
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    Findingcitation
    § MCTGs as alternative brain energy fuel

    Decanoate facilitates glycolysis and lactate formation in astrocytes thereby providing fuel to neurons and improving mitochondrial energy metabolism.

    “Decanoate facilitates glycolysis and lactate formation in astrocytes thereby providing fuel to neurons (Thevenet et al. 2016) and improving mitochondrial energy metabolism (Tan et al. 2017).”
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    Findingcitation
    § MCTGs as alternative brain energy fuel

    Octanoate was shown to promote ketogenesis in astrocytes and to inhibit brain glycolysis in mice by reducing the maximal activity of the rate-limiting enzyme PFK.

    “Octanoate was shown to promote ketogenesis in astrocytes (Thevenet et al. 2016) and to inhibit brain glycolysis in mice (McDonald et al. 2014) by reducing the maximal activity of the ratelimiting enzyme PFK (Tan et al. 2017).”
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    Findingnone given
    § Role of pericytes in the BBB and glucose homeostasis

    Glucose intake of pericytes is four times higher than of endothelial cells, but similar to that of astrocytes, suggesting potential astrocyte/pericyte complementary roles in maintaining glucose homeostasis in the brain.

    “Moreover, glucose intake of pericytes is four times higher than of endothelial cells, but similar to that of astrocytes, suggesting potential astrocyte/ pericyte complementary roles in maintaining glucose homeostasis in the brain.”
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    Findingcitation
    § Glycogen metabolism

    Vasoactive intestinal polypeptide as well as norepinephrine induce glycogenolysis in murine cortex.

    “Interestingly, vasoactive intestinal polypeptide as well as norepinephrine induce glycogenolysis in murine cortex (Magistretti et al. 1981).”
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    Premisecitation
    § Why does the brain have high energy expenditure?

    These outstanding social skills correlated with increased intelligence and imposed higher nutrient requirements.

    “These outstanding social skills correlated with increased intelligence and are highlighted as necessary for more effective foraging and the exploitation of high-energy food; however, at the same time, the evolvement of these capabilities also imposes higher nutrient requirements (summarized in Dunbar & Shulz, 2017).”
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    Premisecitation
    § Why does the brain have high energy expenditure?

    The human brain accounts for 20% of oxygen consumption and 25% of glucose utilization, although it amounts to only 2% of body weight.

    “The human brain, however, accounts for 20% of oxygen (O 2 ) consumption and 25% of glucose utilization, although it amounts to only 2% of body weight (Sokoloff et al. 1977).”
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    Premisecitation
    § Why does the brain have high energy expenditure?

    During humanization, multifaceted social behaviors evolved, such as formation of complex social groups, long-term parental investment, and cooperative foraging strategies.

    “During humanization, multifaceted social behaviors evolved, such as formation of complex social groups, long-term parental investment, and cooperative foraging strategies.”
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    Premisecitation
    § Why does the brain have high energy expenditure?

    According to Karbowski's estimates, cerebral energy per neuron increases with brain size.

    “According to Karbowski's estimates, which are based on the assumption of uniform scaling of neuronal density across species, cerebral energy per neuron increases with brain size (Karbowski 2009).”
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    Interpretationnone given
    § Abstract

    Disturbances to the energetic balance, to mitochondria quality control, or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS.

    “Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS.”
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    Interpretationreasoning
    § Presynaptic terminals

    In light of the distal location of nerve terminals from cell bodies, synapses must rely on local ATP supplies, leaving them highly susceptible to mitochondriopathies.

    “In light of the distal location of nerve terminals from cell bodies, synapses must rely on local ATP supplies, leaving them highly susceptible to mitochondriopathies.”
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    Premisenone given
    § Synaptic plasticity

    Transmission failure was rescued at high stimulation frequencies by adding ATP exogenously and provided evidence that the reserve pool recruitment depends on ATPmit production downstream of PKA signaling.

    “Moreover, transmission failure was rescued at high stimulation frequencies by adding ATP exogenously and provided evidence that the reserve pool recruitment depends on ATPmit production downstream of PKA (protein kinase A) signaling.”
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    Premisereasoning
    § Presynaptic terminals

    Monitoring of ATPpresyn during AP firing in the absence of external Ca2+ revealed that ATP utilized by the Na+/K+-ATPase alone represents a relatively small energy burden compared to downstream vesicle cycle processes at presynaptic terminals and that AP firing can persist even during phases of acute ATP synthesis blockade.

    “The monitoring of ATPpresyn during AP firing in the absence of external Ca 2+ revealed that ATP utilized by the Na + /K + -ATPase alone represents a relatively small energy burden compared to downstream vesicle cycle processes at presynaptic terminals and that AP firing can persist even during phases of acute ATP synthesis blockade.”
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    § Why does the brain have high energy expenditure?

    Plasticity of synapses can be mediated by changes in Ca2+ concentration and/or the number of neurotransmitter receptors.

    “Plasticity of synapses can be mediated by changes in Ca 2+ concentration and/or the number of neurotransmitter receptors.”
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    § Presynaptic terminals

    ATPpresyn levels are reduced by insufficiency of either glycolysis or mitochondrial function, indicating the requirement of activity-driven ATP synthesis to meet the energy demands of synaptic function.

    “ATPpresyn levels are reduced by insufficiency of either glycolysis or mitochondrial function, indicating the requirement of activity-driven ATP synthesis to meet the energy demands of synaptic function.”
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    § Presynaptic terminals

    Inhibition of glycolysis is accompanied by a reduction in endocytosis and a shift in remaining vesicular pH to more alkaline values.

    “Inhibition of glycolysis is accompanied by a reduction in endocytosis and a shift in remaining vesicular pH to more alkaline values.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Synaptic plasticity

    Long-term potentiation (LTP), which can be triggered by activation of the postsynaptic NMDA receptors and insertion of more AMPA receptors into the postsynaptic membrane, enhances ATP supplement to potentiated synapses and energy consumption at postsynapses.

    “For example, longterm potentiation (LTP), which can be triggered by activation of the postsynaptic NMDA receptors and insertion of more a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors into the postsynaptic membrane, enhances ATP supplement to potentiated synapses and energy consumption at postsynapses (Wieraszko 1982).”
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    Interpretationreasoning
    § Presynaptic terminals

    ATPpresyn demand and activity-induced ATP synthesis should be synchronous and are essential for the maintenance of normal synaptic plasticity function.

    “Therefore, ATPpresyn demand and activity-induced ATP synthesis should be synchronous and are essential for the maintenance of normal synaptic plasticity function.”
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    Premisecitation
    § Presynaptic terminals

    The arrest of endocytosis at energy deficit conditions depends on the mechanochemical enzyme dynamin, which mediates membrane fission and depends cooperatively on synthesized guanosine triphosphate using ATP.

    “The arrest of endocytosis at energy deficit conditions depends on the mechanochemical enzyme dynamin, which mediates membrane fission and depends cooperatively on synthesized guanosine triphosphate using ATP (Rangaraju et al. 2014).”
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    Premisenone given
    § Why does the brain have high energy expenditure?

    Not only the generation of action potentials, postsynaptic ion fluxes, presynaptic Ca2+ entry, transmitter reuptake, and vesicle cycling but also the maintenance of the resting potential is a costly cellular neuronal function.

    “Not only the generation of action potentials (AP), postsynaptic ion fluxes, presynaptic Ca 2+ entry, transmitter reuptake, and vesicle cycling but also the maintenance of the resting potential is a costly cellular neuronal function.”
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    Premisereasoning
    § Presynaptic terminals

    Completely blocking exocytosis does not significantly affect Ca2+ influx during neuronal APs, suggesting that the synaptic vesicle cycle consumes most ATPpresyn.

    “Completely blocking exocytosis does not significantly affect Ca 2+ influx during neuronal APs, suggesting that the synaptic vesicle cycle consumes most ATPpresyn.”
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    Premisecitation
    § Presynaptic terminals

    The distribution of mitochondria inside a cell is positively correlated with signaling-related energy usage predicted by Attwell and Laughlin (2001), and is higher in soma plus dendrites (62%) than in axon terminals (36%).

    “highlighted by the positive correlation between the signaling-related energy usage predicted by Attwell and Laughlin (2001) and the distribution of mitochondria inside a cell, which was demonstrated to be higher in soma plus dendrites (62%) than in axon terminals (36%) (Wong-Riley 1989).”
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    § Postsynaptic terminals

    Activation of postsynaptic G protein-coupled receptors, such as metabotropic glutamate receptors (mGluR), triggers downstream events, which constrain ATP usage.

    “Moreover, activation of postsynaptic G protein-coupled receptors, such as metabotropic glutamate receptors (mGluR), triggers downstream events, which constrain ATP usage.”
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    Premisecitation
    § Synaptic plasticity

    Mutations in Drosophila dynamin-related protein 1 (Drp1) depleted mitochondria from motor nerve terminals and interfered with mobilization of the reserve pool of synaptic vesicles and maintenance of neurotransmission.

    “Additionally, mutations in Drosophila dynamin-related protein 1 (Drp1) depleted mitochondria from motor nerve terminals and interfered with mobilization of the reserve pool of synaptic vesicles and maintenance of neurotransmission (Verstreken et al. 2005).”
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    Premisecitation
    § Synaptic plasticity

    Inhibition of ATPmit production interfered with synaptic accumulation of mitochondria and subsequently abolished synaptic potentiation at the Drosophila neuromuscular junction.

    “Inhibition of ATPmit production interfered with synaptic accumulation of mitochondria and subsequently abolished synaptic potentiation at the Drosophila neuromuscular junction (Tong 2007).”
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    Premisecitation
    § Action potential (AP) generation and propagation

    Direct experimental data in rat hippocampal nonmyelinated mossy fibers showed a minimal temporal overlap between the entry of Na+ and the outflow of K+ during an AP which results in one-third less energy necessary to elicit depolarization than in the Hodgkin-Huxley model, pointing to an AP:PSC ratio of 20:80%.

    “direct experimental data in rat hippocampal nonmyelinated mossy fibers showed a minimal temporal overlap between the entry of Na + and the outflow of K + during an AP which results in one-third less energy necessary to elicit depolarization than in the Hodgkin-Huxley model, pointing to an AP : PSC ratio of 20 : 80% (Alle et al. 2009).”
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    Premisenone given
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Pyruvate can either enter the TCA cycle via pyruvate dehydrogenase and be metabolized via OxPhos in mitochondria to generate ATP or be converted to lactate or alanine by LDH or aminotransferase, respectively.

    “Then, pyruvate can either enter the TCA cycle via pyruvate dehydrogenase and be metabolized via OxPhos in mitochondria to generate ATP or be converted to lactate or alanine by LDH or aminotransferase, respectively.”
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    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Muscle-type LDH5 having a greater Vmax is better equipped at converting pyruvate to lactate and supports higher glycolytic rates, but LDH1 exhibits a lower Km and is inhibited by low concentrations of pyruvate and by lactate.

    “Furthermore, the muscle-type LDH5 having a greater V max is better equipped at converting pyruvate to lactate and supports higher glycolytic rates, but LDH1 exhibits a lower K m and is inhibited by low concentrations of pyruvate and by lactate.”
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    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Lactate cannot diffuse passively across the BBB; it needs to be produced in situ within the brain and efficiently transported between cells.

    “Since lactate cannot diffuse passively across the BBB, it needs to be produced in situ within the brain and efficiently transported between cells (Fig. 2).”
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    Interpretationreasoning
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Higher expression of LDH5 suggests a higher rate of glycolysis in astrocytes and higher expression of LDH1 suggests lactate utilization as an energy source in neurons.

    “In summary, higher expression of LDH5 suggests a higher rate of glycolysis in astrocytes and higher expression of LDH1 suggests lactate utilization as an energy source in neurons.”
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    Interpretationreasoning
    § Glucose

    The K+-mediated mechanism is a general hallmark of neurometabolic coupling.

    “This K + -mediated mechanism was suggested to be a general hallmark of neurometabolic coupling”
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    • Rests on an assumption: K+ is released at nodes of Ranvier during AP propagation, at serotonergic synapses, or at the cholinergic neuromuscular junction.

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    Premisecitation
    § Maintaining resting potential

    The spike-related energy expenditure is only 13% of total energy usage in human neocortex, attributing 28% and 10% to maintain the resting potential in neurons and glia, respectively, and the remaining to non-signaling ('housekeeping') processes.

    “Lennie (2003) estimated that the spike-related energy expenditure is only 13% of total energy usage in human neocortex, attributing 28% and 10% to maintain the resting potential in neurons and glia, respectively, and the remaining to non-signaling ('housekeeping') processes (Lennie 2003).”
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    Premisecitation
    § Action potential (AP) generation and propagation

    The classical Hodgkin-Huxley model for AP generation in the squid axon and a number of assumptions such as treating all neurons as identical led to an assumed energy expenditure ratio for AP and PSC of 58:42%.

    “while the classical Hodgkin-Huxley model for AP generation in the squid axon and a number of assumptions such as treating all neurons as identical (Attwell and Laughlin 2001) led to an assumed energy expenditure ratio for AP and PSC of 58 :”
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    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    MCT2 and MCT4 are selectively expressed by neurons and astrocytes, respectively, while MCT1 is expressed in astrocytes, oligodendrocytes, and endothelial cells of blood vessels.

    “While MCT2 and MCT4 are selectively expressed by neurons and astrocytes, respectively, MCT1 is expressed in astrocytes, oligodendrocytes, and endothelial cells of blood vessels (Debernardi et al. 2003;Pierre and Pellerin 2005;Rinholm et al. 2011).”
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    Premisecitation
    § Action potential (AP) generation and propagation

    After one AP, rodent cortical neurons require between ~4-8 x 10^8 ATP molecules to restore the Na+ and K+ gradient through the Na+/K+-ATPase, suggesting the metabolic cost of AP signaling is the second largest after synaptic transmission.

    “It has been estimated that after one AP, rodent cortical neurons require between ~4-8 9 10 8 ATP molecules to restore the Na + and K + gradient through the Na + /K + -ATPase, suggesting the metabolic cost of AP signaling is the second largest after synaptic transmission (Lennie 2003;Hallermann et al. 2012).”
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    • cites Lennie 2003

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    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Conversion of lactate to pyruvate, catalyzed by LDH, is essential as it then provides 18 ATPs via OxPhos.

    “Additionally, as lactate cannot be utilized directly, conversion of lactate to pyruvate, catalyzed by LDH, is essential as it then provides 18 ATPs via OxPhos (Pellerin and Magistretti 1994;Magistretti 2006).”
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    Premisecitation
    § Ketone bodies

    β-OHB may increase by fasting or starvation to 5-6 mM, and to ~25 mM by dietary intervention or diabetic ketosis.

    “This may increase by fasting or starvation to 5-6 mM (Owen et al. 1967), and to ~25 mM by dietary intervention or diabetic ketosis (Garber et al. 1974;Saudubray et al. 1981;Bonnefont et al. 1990;Mitchell et al. 1995).”
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    • cites Saudubray et al. 1981

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  • May combine two claims.

    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    According to the ANLS hypothesis, astrocytes serve as a 'lactate source' whereas neurons serve as a 'lactate sink'.

    “According to this, astrocytes serve as a 'lactate source' whereas neurons serve as a 'lactate sink' (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pellerin and Magistretti 1994

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  • May combine two claims.

    Interpretationreasoning
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    When neuronal activity intensifies, astrocytes increase their glucose uptake, thus increasing the rate of glycolysis and lactate release into the extracellular space.

    “In this context, when neuronal activity intensifies, astrocytes increase their glucose uptake, thus increasing the rate of glycolysis and lactate release into the extracellular space.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Ketone bodies

    Mild elevation of blood ketone bodies occurs during the process of normal aging.

    “Additionally, mild elevation of blood ketone bodies occurs during the process of normal aging (Sengupta et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sengupta et al. 2010

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    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    When the activity of the MAS is limited, NAD+ cannot be regenerated for glycolysis and NADH is not further oxidized in the electron transport chain (ETC), leading to an increase in cytosolic NADH concentration and a decrease in glycolysis and OxPhos.

    “when the activity of the MAS is limited (due to Ca 2+ -induced activation of the a-KG dehydrogenase, which competes with the malate/a-KG carrier for substrate), NAD + cannot be regenerated for glycolysis and NADH is not further oxidized in the electron transport chain (ETC), leading to an increase in cytosolic NADH concentration and a decrease in glycolysis and OxPhos.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bak et al. 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Bak and colleagues argue that oxidative metabolism of lactate within neurons only occurs during repolarization (and in the period between depolarizations) rather than during neurotransmission activity; and that neurons use lactate as an 'opportunistic' substrate when it is present.

    “In opposition to the ANLS hypothesis, Bak and colleagues argue that oxidative metabolism of lactate within neurons only occurs during repolarization (and in the period between depolarizations) rather than during neurotransmission activity (Bak et al. 2009); and that neurons use lactate as an 'opportunistic' substrate when it is present (Bak and Walls 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bak et al. 2009

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    • cites Bak and Walls 2018

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    According to the model proposed by Bak et al., elevated neurotransmission may not increase oxidative metabolism of lactate; it decreases possibly because of a depolarization-induced increase in intracellular Ca2+ concentration and a putative limitation of the MAS.

    “According to the model proposed by Bak et al., elevated neurotransmission may not increase oxidative metabolism of lactate; it decreases possibly because of a depolarization-induced increase in intracellular Ca 2+ concentration and a putative limitation of the MAS”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bak et al. 2009

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  • May combine two claims.

    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Due to unmet O2 demand, plasma lactate levels are enhanced by conversion of pyruvate to lactate, which is an important step to regenerate NAD+, an essential substrate to carry out glycolysis and release ATP in the muscle.

    “However, due to unmet O 2 demand, plasma lactate levels are enhanced by conversion of pyruvate to lactate, which is an important step to regenerate NAD + , an essential substrate to carry out glycolysis and release ATP in the muscle (Lucas-Cuevas et al. 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lucas-Cuevas et al. 2015

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Strenuous physical activity increases O2 demand by the skeletal muscles leading to increased heart rate and respiration.

    “Strenuous physical activity increases O 2 demand by the skeletal muscles leading to increased heart rate and respiration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    The ANLS concept has been critically viewed and challenged due in part to contradictory results obtained in different experimental settings, and to the lack of a consensus-based method for real-time monitoring of metabolic dynamics at cellular resolution.

    “However, the ANLS concept has been critically viewed and challenged due in part to contradictory results obtained in different experimental settings, and to the lack of a consensus-based method for real-time monitoring of metabolic dynamics at cellular resolution.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    The ANLS concept explains the role of lactate as an important energy source for brain function as well as defines the strong metabolic association between astrocytes and neurons.

    “The ANLS concept explains the role of lactate as an important energy source for brain function as well as defines the strong metabolic association between astrocytes and neurons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    A sodium gradient drives glutamate exchange, where one glutamate is co-transported with three Na+ ions, thereby increasing the concentration of Na+ within astrocytes.

    “A sodium gradient drives this glutamate exchange, where one glutamate is co-transported with three Na + ions, thereby increasing the concentration of Na + within astrocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    These results together with several converging lines of evidence suggest a critical role for alterations in global and regional brain metabolism in the pathogenesis of neurodegenerative diseases, indicating that physical activity could provide clinical benefit.

    “These results together with several converging lines of evidence suggest a critical role for alterations in global and regional brain metabolism in the pathogenesis of neurodegenerative diseases, indicating that physical activity could provide clinical benefit.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § MCTGs as alternative brain energy fuel

    MCTGs are fatty acids with 7-12 carbon chain length; the most common MCTGs include heptanoate (C7), octanoate (C8), and decanoate (C10).

    “MCTGs are fatty acids with 7-12 carbon chain length; the most common MCTGs include heptanoate (C7), octanoate (C8), and decanoate (C10) (Sch€ onfeld and Wojtczak 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sch€ onfeld and Wojtczak 2016

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Most neurodegenerative diseases, as well as any other adverse changes in the brain, have notable changes in the ANLS and lead to imbalances in neurometabolic coupling.

    “It is suggested that most of the neurodegenerative diseases, as well as any other adverse changes in the brain, have notable changes in the ANLS and lead to imbalances in neurometabolic coupling (B elanger et al. 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites B elanger et al. 2011

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    PET with the glucose analog F fluorodeoxyglucose (FDG) is commonly used as a clinical diagnostic measure for local glucose metabolism.

    “To further build upon these findings, for both research and diagnose purposes, positron emission tomography (PET) with the glucose analog F fluorodeoxyglucose (FDG) is commonly used as clinical diagnostic measure for local glucose metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    A higher Na+ concentration within astrocytes leads to the activation of the α2 subunit of the Na+/K+-ATPase which results in glycolysis stimulation.

    “A higher Na + concentration within astrocytes leads to the activation of the a 2 subunit of the Na + /K + -ATPase which results in glycolysis stimulation (Mason 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mason 2017

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Ketone bodies

    The concentration of β-OHB in plasma under healthy, fasted conditions is relatively low with reference values reported ~0.04 mM-0.08 mM.

    “The concentration of b-OHB in plasma under healthy, fasted conditions is relatively low with reference values reported ~0.04 mM-0.08 mM (Hansen and Freier 1978).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hansen and Freier 1978

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Increased neuronal activity corresponds to an increased release of glutamate from presynaptic vesicles into the synapse.

    “Increased neuronal activity corresponds to an increased release of glutamate from presynaptic vesicles into the synapse.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Ketone bodies

    β-Hydroxybutyrate (β-OHB) is a metabolic intermediate that constitutes ~70% of ketone bodies produced in liver mitochondria mainly from the oxidation of fatty acids released from adipose tissue.

    “b-Hydroxybutyrate (b-OHB) is a metabolic intermediate that constitutes ~70% of ketone bodies produced in liver mitochondria mainly from the oxidation of fatty acids released from adipose tissue (Persson 1970).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Persson 1970

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    Premisecitation
    § Ketone bodies

    Under normal physiological conditions, monocarboxylates cross the BBB with poor efficiency, but under starvation, the amount of ketones present in the blood and expression of MCTs in cells forming the BBB are increased.

    “Under normal physiological conditions, monocarboxylates cross the BBB with poor efficiency, but under starvation, the amount of ketones present in the blood and expression of MCTs in cells forming the BBB are increased (Hasselbalch et al. 1995).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hasselbalch et al. 1995

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  • May combine two claims.

    Interpretationreasoning
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    This stimulation leads to the production of lactate which is used as a substitute energy substrate by neurons.

    “This stimulation leads to the production of lactate which is used as a substitute energy substrate by neurons.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Lactate and the Astrocyte-Neuron Lactate Shuttle hypothesis

    Some authors argue that neurons prefer lactate over glucose; others claim neurons are well equipped to metabolize glucose in an activity-dependent manner, which clearly opposes the tight coupling of astrocytes to synaptic activity.

    “For example, while some authors argue that neurons prefer lactate over glucose (Bouzier-Sore et al. 2003); others claim neurons are well equipped to metabolize glucose in an activity-dependent manner (Bak et al. 2009), which clearly opposes to the tight coupling of astrocytes to synaptic activity (Ruminot et al. 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bouzier-Sore et al. 2003

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    • cites Bak et al. 2009

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    • cites Ruminot et al. 2017

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § MCTGs as alternative brain energy fuel

    Triheptanoin, a triglyceride of heptanoate, generates three molecules of heptanoate upon hydrolysis.

    “Triheptanoin, a triglyceride of heptanoate, generates three molecules of heptanoate upon hydrolysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Role of pericytes in the BBB and glucose homeostasis

    Pericytes are imperative for normal CNS functioning and have important roles in angiogenesis, vessel stabilization, endothelial cell regulation, and maintenance of the BBB.

    “Pericytes are imperative for normal CNS functioning and have important roles in angiogenesis, vessel stabilization, endothelial cell regulation, and maintenance of the BBB (Fisher 2009;Hill et al. 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fisher 2009

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    • cites Hill et al. 2014

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    Premisecitation
    § MCTGs as alternative brain energy fuel

    Owing to their smaller size, MCTGs can readily diffuse into the brain as they do not require carnitine transporters unlike long chain fatty acids.

    “Owing to their smaller size, MCTGs can readily diffuse into the brain as they do not require carnitine transporters unlike long chain fatty acids (Oldendorf 1973;Kuge et al. 1995).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Oldendorf 1973

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    • cites Kuge et al. 1995

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    Premisecitation
    § MCTGs as alternative brain energy fuel

    Heptanoate can directly enter into the brain or can be degraded into C5 ketones in the liver.

    “Heptanoate can directly enter into the brain or can be degraded into C5 ketones in the liver (Marin-Valencia et al. 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Marin-Valencia et al. 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Pericytes

    Pericytes may also be found around the lymphatic capillaries in cases of developmental abnormalities.

    “They may also be found around the lymphatic capillaries in cases of developmental abnormalities (Petrova et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Petrova et al. 2004

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    Premisecitation
    § Role of pericytes in the BBB and glucose homeostasis

    Reports suggest that the pericyte-endothelial interaction regulates the basement membrane and the anatomical proximity between pericytes and endothelial cells indicates a probable role of pericytes in paracrine or juxtacrine signaling.

    “Reports suggest that the pericyte-endothelial interaction regulates the basement membrane (Stratman et al. 2009(Stratman et al. , 2010) ) and the anatomical proximity between pericytes and endothelial cells indicates a probable role of pericytes in paracrine or juxtacrine signaling, as pericytes have been proposed to be involved in several signaling pathways including Angiopoietin-1, transforming”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Stratman et al. 2009

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    • cites Stratman et al. 2010

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    • cites Gaengel et al. 2009

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    Premisecitation
    § Pericytes

    The perivascular location and morphology of pericytes led to the suggestion that they may be contractile cells involved in regulation of capillary blood flow in response to vasoactive agents and neural activity.

    “The perivascular location and morphology of pericytes led to the suggestion that they may be contractile cells involved in regulation of capillary blood flow in response to vasoactive agents and neural activity (Sweeney et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sweeney et al. 2016

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    Premisecitation
    § MCTGs as alternative brain energy fuel

    C4 ketones and MCTGs can be further metabolized to acetyl-coenzyme A (CoA) and enter into the TCA cycle, primarily in astrocytes.

    “C4 ketones and MCTGs can be further metabolized to acetyl-coenzyme A (CoA) and enter into the TCA cycle, primarily in astrocytes (Edmond et al. 1987;Marin-Valencia et al. 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Edmond et al. 1987

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    • cites Marin-Valencia et al. 2013

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    Premisenone given
    § MCTGs as alternative brain energy fuel

    The C5 ketones get converted into propionyl CoA, an anaplerotic molecule which can be carboxylated to succinyl coenzyme A (CoA) to feed the TCA cycle.

    “The C5 ketones get converted into propionyl CoA, an anaplerotic molecule which can be carboxylated to succinyl coenzyme A (CoA) to feed the TCA cycle.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Astrocytes

    G6P can then be channeled into the glycolytic pathway to produce pyruvate, metabolized to glucose-1-phosphate for the synthesis of glycogen, or used in the PPP.

    “G6P can then be channeled into the glycolytic pathway to produce pyruvate, metabolized to glucose-1-phosphate for the synthesis of glycogen (Cataldo and Broadwell 1986;Dienel and Cruz 2015), or used in the PPP (Dringen et al. 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cataldo and Broadwell 1986

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    • cites Dienel and Cruz 2015

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    • cites Dringen et al. 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § Astrocytes

    This neurometabolic coupling is a salient physiological characteristic of the brain function and has formed the basis for understanding neuroenergetics.

    “This neurometabolic coupling is a salient physiological characteristic of the brain function and has formed the basis for understanding neuroenergetics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Astrocytes

    While the PPP is only a minor contributor to the total glucose oxidation, it generates NADPH, an important molecule for maintaining the antioxidant-reduced glutathione, as well as precursors for nucleotide synthesis.

    “While the PPP is only a minor contributor to the total glucose oxidation, it generates NADPH, an important molecule for maintaining the antioxidant-reduced glutathione, as well as precursors for nucleotide synthesis (Dringen et al. 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dringen et al. 2007

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    Premisecitation
    § Astrocytes

    Astrocytes are the most abundant glial cells in the brain and display a number of active roles critical for CNS function, including regulation of neurotransmitters, supplying substrates to neurons for OxPhos, maintaining water homeostasis, and regulating blood supply to meet neuronal energy demand.

    “Astrocytes are the most abundant glial cells in the brain and display a number of active roles critical for CNS function (Nedergaard et al. 2003;Barros et al. 2018b), including regulation of neurotransmitters (Anderson and Swanson 2000), supplying substrates to neurons for OxPhos (Pellerin et al. 1998), maintaining water homeostasis (Simard and Nedergaard 2004;Salman et al. 2017a), and regulating”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Nedergaard et al. 2003

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    • cites Barros et al. 2018b

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    • cites Anderson and Swanson 2000

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    Premisecitation
    § Astrocytes

    Astrocytes have extensive processes originating from the soma; some of these ensheath synapses forming the 'tripartite synapse', while others known as 'endfeet' surround the brain arteries and capillaries.

    “Astrocytes have extensive processes originating from the soma; some of these ensheath synapses (Ventura and Harris 1999) forming the 'tripartite synapse', while others known as 'endfeet' surround the brain arteries and capillaries (Araque et al. 1999;Oberheim et al. 2006;Barros et al. 2018b).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ventura and Harris 1999

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    • cites Araque et al. 1999

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    • cites Oberheim et al. 2006

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  • May combine two claims.

    Interpretationnone given
    § Glycogen metabolism

    This signal-induced regulation of glucose supply is thought to act in a complementary way; while vasoactive intestinal polypeptide acts locally within cortical columns, norepinephrine can control glycogen metabolism across adjacent columns.

    “This signal-induced regulation of glucose supply is thought to act in a complementary way; while vasoactive intestinal polypeptide acts locally within cortical columns, norepinephrine can control glycogen metabolism across adjacent columns.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Astrocytes

    In addition to glucose, astrocytes can efficiently use alternative energy substrates, such as mannose; however, other carbohydrates like fructose or galactose are considered to be poor substrates in astrocytes.

    “In addition to glucose, astrocytes can efficiently use alternative energy substrates, such as mannose (Dringen et al. 1993); however, other carbohydrates like fructose or galactose are considered to be poor substrates in astrocytes (Dringen et al. 1993).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dringen et al. 1993

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    Premisecitation
    § Glycogen metabolism

    Astrocytic glycogenolysis is activated by extracellular increase in neurotransmitter concentrations as well as changes in the K+ homeostasis following neuronal activity.

    “Astrocytic glycogenolysis is activated by extracellular increase in neurotransmitter concentrations as well as changes in the K + homeostasis following neuronal activity (Hof et al. 1988;Sickmann et al. 2009;Wang et al. 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hof et al. 1988

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    • cites Sickmann et al. 2009

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    • cites Wang et al. 2012

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    Premisecitation
    § Glycogen metabolism

    Glycogen is predominantly found in astrocytes and seems to be connected to specific organelles and nonrandomly distributed.

    “Glycogen is predominantly found in astrocytes and seems to be connected to specific organelles and nonrandomly distributed (Cal ı et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cal ı et al. 2016

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    Premisecitation
    § Glycogen metabolism

    The glycogen pool is dynamic and rapidly responds to changes in cerebral energetic demands by undergoing constant degradation and resynthesis, facilitated by glycogen synthase and glycogen phosphorylase expressed by astrocytes.

    “The glycogen pool is dynamic and rapidly responds to changes in cerebral energetic demands by undergoing constant degradation and resynthesis (Swanson 1992), facilitated by glycogen synthase and glycogen phosphorylase expressed by astrocytes (Pellegri et al. 1996;Brown and Ransom 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Swanson 1992

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    • cites Pellegri et al. 1996

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    • cites Brown and Ransom 2007

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    Premisecitation
    § Microglia

    Microglia can mount a molecular defense through the production of bioactive molecules that can be detrimental in some circumstances, such as when remaining primed in a disease state and dysfunctional in response to a secondary injury, leading to loss of neural circuits.

    “Microglia can mount a molecular defense through the production of bioactive molecules that can be beneficial in some circumstances (i.e., phagocytosis of aberrant cells posing a threat to the CNS) and detrimental in others (i.e., when remaining primed in a disease state and being dysfunctional in response to a secondary injury, which can lead to loss of neural circuits) (Kettenmann et al. 2011;Dan”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kettenmann et al. 2011

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    • cites Daneman 2012

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    • cites Koss et al. 2019

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    Premisecitation
    § Oligodendrocytes

    While myelination is the primary function of oligodendrocytes, they also provide trophic support to neurons by secreting a wide variety of neurotrophins, including insulinlike growth factor-1, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor.

    “While myelination is the primary function of oligodendrocytes, they also provide trophic support to neurons by secreting a wide variety of neurotrophins, including insulinlike growth factor-1, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor (Bradl and Lassmann 2010;Saab et al. 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bradl and Lassmann 2010

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    • cites Saab et al. 2013

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    Premisecitation
    § Microglia

    Microglia interact with neurons (scanning synapses) and contribute to the structure of neuronal networks and connectivity.

    “Microglia interact with neurons (i.e., scanning synapses) and thus contribute to the structure of neuronal networks and connectivity (Kettenmann et al. 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kettenmann et al. 2011

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    Premisecitation
    § Oligodendrocytes as energy consumers

    Myelination is energetically costly and the metabolic costs of generating enough lipid and protein for myelin synthesis may be higher than the energy saved by accelerated axonal conduction.

    “Conversely, myelination is energetically costly and the metabolic costs of generating enough lipid and protein for myelin synthesis may be higher than the energy saved by accelerated axonal conduction (Nave and Werner 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nave and Werner 2014

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    Premisecitation
    § Microglia

    When activated, as indicated by a change in morphology toward increased soma size and thicker proximal ramifications, microglia can migrate to the site of injury and proliferate.

    “When activated, as indicated by a change in morphology toward an increased soma size and thicker proximal ramifications, microglia can migrate to the site of injury and proliferate (Bernhart et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bernhart et al. 2010

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    Interpretationcitation
    § Oligodendrocytes as energy consumers

    The primary function of myelination is not to save energy, but rather to allow fast nerve conduction, thereby increasing information processing and improving cognitive power.

    “Therefore, the primary function of myelination is not to save energy, but rather to allow fast nerve conduction, thereby increasing information processing and improving cognitive power (Harris and Attwell 2012;Nave and Werner 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Harris and Attwell 2012

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    • cites Nave and Werner 2014

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    Premisecitation
    § Microglia

    Microglia are cells of mesodermal origin that migrate into the CNS during embryonic development.

    “Microglia are cells of mesodermal origin that migrate into the CNS during embryonic development (Hickey and Kimura 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hickey and Kimura 1988

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    Premisenone given
    § Oligodendrocytes

    Myelin acts as an electrical insulator by increasing the membrane resistance and decreasing membrane capacitance, resulting in increased conduction velocity while reducing axonal size requirements and neuronal metabolic demand.

    “Myelin acts as an electrical insulator by increasing the membrane resistance and decreasing membrane capacitance, resulting in increased conduction velocity while reducing axonal size requirements and neuronal metabolic demand.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Microglial energy sources and metabolism

    Glucose is imperative for microglia survival and can enter microglia via transporters GLUT1, GLUT3, GLUT4, and GLUT5.

    “Glucose is imperative for microglia survival and can enter microglia via transporters GLUT1, GLUT3, GLUT4, and GLUT5 (Payne et al. 1997;Wang et al. 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Payne et al. 1997

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    • cites Wang et al. 2019

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    Premisecitation
    § Microglial energy sources and metabolism

    G protein-coupled receptor 120 binds unsaturated fatty acids and is possibly involved in their anti-inflammatory effects.

    “G protein-coupled receptor 120 is known to bind unsaturated fatty acids and is possibly involved in their anti-inflammatory effects (Kalsbeek et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kalsbeek et al. 2016

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    Premisecitation
    § Aging

    Age-related decline in brain glucose uptake exceeds that of O2 utilization, causing a loss of brain aerobic glycolysis.

    “A recent study from Goyal et al. (2017) showed that agerelated decline in brain glucose uptake exceeds that of O 2 utilization, causing a loss of brain aerobic glycolysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Goyal et al. (2017)

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    Premisecitation
    § Microglial energy sources and metabolism

    GLUT5 is a very poor transporter of glucose and facilitates the passage of fructose across the plasma membrane.

    “Conversely, GLUT5, exclusively expressed in microglial cells of the human and rat brain, is a very poor transporter of glucose and has been shown to facilitate the passage of fructose across the plasma membrane (Payne et al. 1997;Horikoshi et al. 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Payne et al. 1997

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    • cites Horikoshi et al. 2003

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    Premisecitation
    § Aging

    Inadequate glucose metabolism can arise from disruptions in supply, transport, or utilization, which likely all contribute to T2DM.

    “This inadequate glucose metabolism can arise from disruptions in supply, transport, or utilization, which likely all contribute to T2DM (Wardelmann et al. 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wardelmann et al. 2019

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    Premisecitation
    § Microglial energy sources and metabolism

    Activation of microglia by ROS, especially nitric oxide (NO), modulates metabolic assembly based on glucose uptake and upregulates both anaerobic glycolysis and OxPhos of PPP.

    “Activation of microglia by ROS, especially nitric oxide (NO), modulates metabolic assembly based on glucose uptake and upregulates both anaerobic glycolysis and OxPhos of PPP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gimeno-Bay on et al. 2014

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    Premisecitation
    § Aging

    These studies have identified increased adenosine monophosphate (AMP), ATP, purine, and pyrimidine levels with the accumulation of these metabolites as hallmarks of multiple neurodegenerative diseases.

    “These studies have identified increased adenosine monophosphate (AMP), ATP, purine, and pyrimidine levels (Ivanisevic et al. 2016) with the accumulation of these metabolites as hallmarks of multiple neurodegenerative diseases (Nyhan 2005;Yin et al. 2014).”
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    • cites Ivanisevic et al. 2016

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    • cites Nyhan 2005

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    • cites Yin et al. 2014

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    Premisecitation
    § Aging

    Studies calculating brain glucose utilization from birth to adulthood have identified that energy metabolism peaks during early childhood and declines during aging.

    “Studies calculating brain glucose utilization over the course of human development, from birth to adulthood, have identified that energy metabolism peaks during early childhood (Kuzawa et al. 2014a) and declines during aging (Kuzawa et al. 2014a(Kuzawa et al. , 2014b;;Skoyles 2014).”
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    • cites Kuzawa et al. 2014a

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    • cites Kuzawa et al. 2014b

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    • cites Skoyles 2014

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    Premisecitation
    § Aging

    Impeded cerebral glucose metabolism has been found in patients with T2DM; a condition commonly observed in Alzheimer patients.

    “Impeded cerebral glucose metabolism has been found in patients with T2DM; a condition commonly observed in Alzheimer patients (see below) (Mosconi et al. 2008;Baker et al. 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mosconi et al. 2008

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    • cites Baker et al. 2011

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    Premisecitation
    § Microglial energy sources and metabolism

    Tissue damage releases ATP which attracts microglia at the site of infection and consumes a vast amount of energy.

    “Tissue damage releases ATP which attracts microglia at the site of infection and consumes a vast amount of energy (Engl and Attwell 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Engl and Attwell 2015

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    Premisecitation
    § Aging

    PPAR transcription factors are widely distributed within the mammalian brain and are involved in regulating the expression of genes involved in energy metabolism.

    “PPAR transcription factors have been shown to be widely distributed within the mammalian brain and to be involved in regulating the expression of genes involved in energy metabolism (Woods et al. 2003;Cimini et al. 2005;Cimini and Cer u 2008), making them strong candidates for possible key regulators of metabolic pathways impacted by brain aging.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Woods et al. 2003

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    • cites Cimini et al. 2005

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    • cites Cimini and Cer u 2008

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  • Classified as probably not a substantial claim.

    Premisecitation
    § Parkinson's disease

    It was proposed that there are intrinsic neuronal features of generating and handling APs that render DA SNpc neurons more susceptible to mitochondrial dysfunction related to PD.

    “It was proposed that there are intrinsic neuronal features of generating and handling APs that render DA SNpc neurons more susceptible to mitochondrial dysfunction related to PD (Surmeier et al. 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Surmeier et al. 2012

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Aging

    It has been suggested that T2DM accelerates AD development through perturbations in brain energy metabolism, advanced glycation end product and ROS production, and synaptic degeneration.

    “It has been suggested that T2DM accelerates AD development through perturbations in brain energy metabolism, advanced glycation end product and ROS production, and synaptic degeneration (Correia et al. 2012;Duarte 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Correia et al. 2012

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    • cites Duarte 2015

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    Premisecitation
    § Aging

    Protein levels of Drp1 are increased in AD and potentiate cell death.

    “It has been demonstrated that protein levels of Drp1 are increased in AD and potentiate cell death (Park et al. 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Park et al. 2014

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    Interpretationreasoning
    § Aging

    Reduction of mitochondrial fission leads to increased occurrences of mitochondrial fusion and results in neuroprotective effects in AD models.

    “Therefore, reduction of mitochondrial fission leads to increased occurrences of mitochondrial fusion and results in neuroprotective effects in AD models (Itoh et al. 2013;Park et al. 2014;Baek et al. 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Itoh et al. 2013

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    • cites Park et al. 2014

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    • cites Baek et al. 2017

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    Premisecitation
    § Aging

    Drp1 is important for mitochondrial quality surveillance and induces mitochondrial fission, which reduces the protein levels of mitofusin (MFN) 1/2 and optic atrophy type 1 (OPA1); GTPases that promote the fusion process.

    “This protein is important for mitochondrial quality surveillance and induces mitochondrial fission, which as a consequence reduces the protein levels of mitofusin (MFN) 1/2 and optic atrophy type 1 (OPA1); GTPases that promote the fusion process (Baek et al. 2017).”
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    • cites Baek et al. 2017

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    Premisecitation
    § Aging

    AMPK inhibition promotes a reduction of GLUT3 and GLUT4 in plasma membranes of hippocampal neurons, reducing ATP production.

    “Furthermore, AMPK inhibition promotes a reduction of GLUT3 and GLUT4 in plasma membranes of hippocampal neurons, reducing ATP production (da Silva et al. 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites da Silva et al. 2017

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Parkinson's disease

    PD is a progressive neurodegenerative disorder characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (with a-synuclein inclusions) in the substantia nigra.

    “Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (with a-synuclein inclusions) in the substantia nigra (Sveinbjornsdottir 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sveinbjornsdottir 2016

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    Premisecitation
    § Aging

    Detection of dysfunctions in cerebral energy metabolism represents a tool for AD diagnosis and understanding of pathophysiological mechanisms.

    “As dysfunctions in cerebral energy metabolism are considered a hallmark of AD, their detection represents a tool for AD diagnosis and understanding of pathophysiological mechanisms (Ferris et al. 1980;Mosconi 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ferris et al. 1980

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    • cites Mosconi 2013

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    Premisecitation
    § Aging

    The mitochondrial cascade hypothesis suggests that accumulated mutations in mtDNA caused by ROS play a pivotal role in mitochondrial dysfunction, which can be an early event in AD.

    “As aging is a major risk factor for the onset of neurodegenerative diseases like AD, the mitochondrial cascade hypothesis (Swerdlow and Khan 2004) suggests that accumulated mutations in mtDNA caused by ROS play a pivotal role in mitochondrial dysfunction (Lin and Beal 2006), which can be an early event in AD (Nunomura et al. 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Swerdlow and Khan 2004

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    • cites Lin and Beal 2006

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    • cites Nunomura et al. 2001

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  • May combine two claims.

    Interpretationnone given
    § Aging

    These neurodegenerative disorders all share a metabolic component which may be a consequence of the disorder or even causally contribute to its occurrence.

    “Diabetic conditions can have a disease-modifying effect for progressive neurodegenerative disorders of the brain like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or multiple sclerosis, all of which involve diverse molecular and cellular mechanisms, yet despite unrelated aetiology, they all share a metabolic component which may be a consequence of the disorder or even”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § Aging

    Diabetic conditions can have a disease-modifying effect for progressive neurodegenerative disorders of the brain like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or multiple sclerosis.

    “Diabetic conditions can have a disease-modifying effect for progressive neurodegenerative disorders of the brain like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or multiple sclerosis, all of which involve diverse molecular and cellular mechanisms, yet despite unrelated aetiology, they all share a metabolic component which may be a consequence of the disorder or even”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Aging

    Ab oligomers reduce hexokinase activity and ATP levels in neuronal cultures.

    “Additionally, Ab oligomers reduce hexokinase activity and ATP levels in neuronal cultures (da Silva et al. 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites da Silva et al. 2017

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Parkinson's disease

    In a large retrospective cohort study, a higher prevalence of PD in patients with T2DM was detected.

    “Interestingly, in a large retrospective cohort study, a higher prevalence of PD in patients with T2DM was detected (De Pablo-Fernandez et al. 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites De Pablo-Fernandez et al. 2018

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    Premisecitation
    § Aging

    18FDG PET has revealed a marked reduction in FDG labeling that correlates with AD progression and is more prominent in brain areas most affected by the disease, including the temporal and occipital lobes.

    “This technique has revealed a marked reduction in FDG labeling that correlates with AD progression and is more prominent in brain areas most affected by the disease, including the temporal and occipital lobes (Marcus et al. 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Marcus et al. 2014

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  • May combine two claims.

    Premisecitation
    § Multiple sclerosis

    Axonal energy failure and disrupted mitochondrial energetics, especially in white matter astrocytes, have been implicated in MS.

    “Axonal energy failure and disrupted mitochondrial energetics, especially in white matter astrocytes, have been implicated in MS (Cambron et al. 2012), highlighted by the absence of b2-adrenoreceptors in the astrocytes of MS patients (Cambron et al. 2012), which impairs the noradrenaline-mediated glycogenolysis necessary to exploit this energy reservoir for neurons and their axons, thus leading to”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cambron et al. 2012

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    Premisecitation
    § Multiple sclerosis

    The absence of b2-adrenoreceptors in the astrocytes of MS patients impairs the noradrenaline-mediated glycogenolysis necessary to exploit this energy reservoir for neurons and their axons, thus leading to disrupted ion gradients that disturb the excitability of axons.

    “Axonal energy failure and disrupted mitochondrial energetics, especially in white matter astrocytes, have been implicated in MS (Cambron et al. 2012), highlighted by the absence of b2-adrenoreceptors in the astrocytes of MS patients (Cambron et al. 2012), which impairs the noradrenaline-mediated glycogenolysis necessary to exploit this energy reservoir for neurons and their axons, thus leading to”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cambron et al. 2012

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    Premisecitation
    § Multiple sclerosis

    Intra-axonal accumulation of calcium activates phospholipases and proteases like calpain, which bring about axonal disintegration, and further leads to energy failure via mitochondrial disruption.

    “Intra-axonal accumulation of calcium activates phospholipases and proteases like calpain, which bring about axonal disintegration, and further leads to energy failure via mitochondrial disruption (Pennisi et al. 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pennisi et al. 2011

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    Interpretationreasoning
    § Traumatic brain injury (TBI) and stroke

    The following long-term depression of cerebral metabolic rate of glucose, indicating reduced glucose uptake and utilization, suggests the inability of the injured brain to meet the increased metabolic demands which could be due to reduced glucose supply, defects in glucose transporter systems, and/or reduced need for glucose.

    “The following long-term depression of cerebral metabolic rate of glucose, indicating reduced glucose uptake and utilization, suggests the inability of the injured brain to meet the increased metabolic demands which could be due to reduced glucose supply (as a consequence of hindered cerebral blood flow, CBF), defects in glucose transporter systems, and/or reduced need for glucose.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Traumatic brain injury (TBI) and stroke

    Changes in CBF in patients with TBI show a strong heterogeneity with some patients showing significantly reduced CBF, while in others, normal CBF values can be seen that persist for days to weeks after injury.

    “However, changes in CBF in patients with TBI show a strong heterogeneity with some patients showing significantly reduced CBF, while in others, normal CBF values can be seen that persist for days to weeks after injury (Bouma et al. 1991;Marion et al. 1991).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bouma et al. 1991

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    • cites Marion et al. 1991

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  • May combine two claims.

    Interpretationreasoning
    § Amyotrophic lateral sclerosis

    These metabolic defects, which comprise also disrupted metabolic interactions between neurons and glial cells, result in impaired mitochondrial oxidative phosphorylation, declined generation of ATP, and subsequent death of neurons as well as non-neuronal cells.

    “These metabolic defects, which comprise also disrupted metabolic interactions between neurons and glial cells (reviewed in Tefera and Borges 2017), result in impaired mitochondrial oxidative phosphorylation, declined generation of ATP, and subsequent death of neurons as well as non-neuronal cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tefera and Borges 2017

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  • May combine two claims.

    Premisecitation
    § Parkinson's disease

    Studies in various animal models of PD reveal that mitochondrial dysfunction in the brain is linked to alterations in mitochondrial morphology, dynamics, mutation of mtDNA, increased proton leak, and decreased rates of electron transfer.

    “Studies in various animal models of PD reveal that mitochondrial dysfunction in the brain is linked to alterations in mitochondrial morphology, dynamics, mutation of mtDNA, increased proton leak (Villeneuve et al. 2016), and decreased rates of electron transfer (Golpich et al. 2017;van der Merwe et al. 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Villeneuve et al. 2016

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    • cites Golpich et al. 2017

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    • cites van der Merwe et al. 2017

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    Premisecitation
    § Traumatic brain injury (TBI) and stroke

    Structural damage causes reduced cerebral blood flow and cell membrane disruption and is accompanied by mitochondrial dysfunction, inflammatory responses and oxidative stress, ionic gradient breakdown, glutamate-mediated excitotoxicity, stress signaling, and ultimately cell death.

    “Structural damage causes reduced cerebral blood flow and cell membrane disruption and is accompanied by mitochondrial dysfunction, inflammatory responses and oxidative stress, ionic gradient breakdown, glutamate-mediated excitotoxicity, stress signaling, and ultimately cell death (Lo et al. 2003;Malik and Dichgans 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lo et al. 2003

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    • cites Malik and Dichgans 2018

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    Premisecitation
    § Parkinson's disease

    These impairments in mitochondria are associated with accumulation of oxidation products of phospholipids and proteins, increased ROS production, increased lipid peroxidation, decreased respiration and membrane potential, decreased capacity for ATP production, and neuronal degeneration due to oxidative damage and energy defects in the aged mammalian brain.

    “These impairments in mitochondria are associated with: accumulation of oxidation products of phospholipids and proteins, increased ROS production, increased lipid peroxidation, decreased respiration and membrane potential, decreased capacity for ATP production, and neuronal degeneration due to oxidative damage and energy defects in the aged mammalian brain (Navarro and Boveris 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Navarro and Boveris 2010

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    Premisecitation
    § Parkinson's disease

    Altered mitochondrial fission may result in synaptic loss and DA neuronal cell loss.

    “Moreover, altered mitochondrial fission may result in synaptic loss and DA neuronal cell loss (Berthet et al. 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Berthet et al. 2014

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    Premisecitation
    § Traumatic brain injury (TBI) and stroke

    Altered ionic balance results in a calcium influx, which in turn leads to the depolarization of the mitochondrial membrane due to the opening of the mitochondrial permeability transition pore and cytochrome c-mediated caspase-dependent apoptosis.

    “Altered ionic balance results in a calcium influx (Kitchen et al. 2015b), which in turn leads to the depolarization of the mitochondrial membrane due to the opening of the mitochondrial permeability transition pore and cytochrome cmediated caspase-dependent apoptosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kitchen et al. 2015b

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    Premisecitation
    § Parkinson's disease

    DA neurons lacking the mitochondrial fusion gene MFN2 display fragmented mitochondria and their transport within the axon is hindered.

    “DA neurons lacking the mitochondrial fusion gene MFN2 display fragmented mitochondria and their transport within the axon is hindered (Anh et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Anh et al. 2012

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  • May combine two claims.

    Interpretationcitation
    § Amyotrophic lateral sclerosis

    These metabolic substrates were able to modify ALS disease progression to varying degrees, signifying the contribution of CNS energy metabolism toward the pathogenesis of the disease and the need for further studies to correct metabolic defects.

    “These metabolic substrates were able to modify ALS disease progression to varying degrees, signifying the contribution of CNS energy metabolism toward the pathogenesis of the disease and the need for further studies to correct metabolic defects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tefera and Borges 2017

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Traumatic brain injury (TBI) and stroke

    It is postulated that the acute phase of hyperglycolysis occurs in order to compensate the increased cellular energy requirement to restore the ionic imbalance and membrane potential.

    “It is postulated that the acute phase of hyperglycolysis occurs in order to compensate the increased cellular energy requirement to restore the ionic imbalance and membrane potential (Karelina and Weil 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Karelina and Weil 2016

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  • May combine two claims.

    Premisecitation
    § Amyotrophic lateral sclerosis

    Several pathogenic mechanisms are believed to contribute to motor neuron death in ALS, including abnormal protein aggregation, oxidative stress, glutamate excitotoxicity, and impaired energy metabolism.

    “Several pathogenic mechanisms are believed to contribute to motor neuron death, including abnormal protein aggregation (Bruijn et al. 1997), oxidative stress (Barber et al. 2006), glutamate excitotoxicity (Rothstein 1995), and impaired energy metabolism (Dupuis et al. 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bruijn et al. 1997

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    • cites Barber et al. 2006

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    • cites Rothstein 1995

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  • May combine two claims.

    Premisecitation
    § Amyotrophic lateral sclerosis

    Numerous preclinical investigations in vitro and in vivo as well as in patients have revealed metabolic irregularities in ALS brains which include reductions in glucose uptake and reduced gene expression of enzymes involved in glycolysis, PPP, TCA cycle, and ETC.

    “Numerous preclinical investigations in vitro and in vivo as well as in patients have revealed metabolic irregularities in ALS brains which include reductions in glucose uptake (Miyazaki et al. 2012) and reduced gene expression of enzymes involved in glycolysis (Ferraiuolo et al. 2011), PPP (Kirby et al. 2005), and TCA cycle (D'Arrigo et al. 2010), as well as the ETC (Ferraiuolo et al. 2011).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Miyazaki et al. 2012

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    • cites Ferraiuolo et al. 2011

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    • cites Kirby et al. 2005

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  • May combine two claims.

    Interpretationcitation
    § Multiple sclerosis

    Energy crisis-driven impaired ATP generation may lead to the failure of important pumps and exchangers like the Na+/K+-ATPase and the Na+/Ca2+ exchanger, leading to increased Na+ and Ca2+ influx in axons and disrupted membrane potential.

    “Functionally, energy crisis-driven impaired ATP generation may lead to the failure of important pumps and exchangers like the Na + /K + -ATPase maintaining the Na + concentration within the axon, which is ATP dependent, and the Na + /Ca 2+ exchanger, which further sustains calcium homeostasis.This leads to an increased Na + and Ca 2+ influx in axons and disrupted membrane potential.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given
    § The importance of maintaining brain energy homeostasis

    Neurodegenerative disorders are not exclusively restricted to neurons but glial cells are indeed a pivotal player.

    “Moreover, neurodegenerative disorders are not exclusively restricted to neurons but glial cells are indeed a pivotal player.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Traumatic brain injury (TBI) and stroke

    TBI is frequently accompanied by ischemia and hypoxia, major but not the only causes of mitochondrial dysfunction after injury.

    “TBI is frequently accompanied by ischemia and hypoxia, major but not the only causes of mitochondrial dysfunction after injury (Carpenter et al. 2015;Patet et al. 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carpenter et al. 2015

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    • cites Patet et al. 2016

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    Premisecitation
    § Costly human brain: evolutionary implications

    GLUT1 expression in human brain was found to be much higher as compared to chimpanzee and macaque brains, but GLUT4 expression is higher in chimpanzee skeletal muscle than in human and macaque muscle.

    “GLUT1 expression in human brain was found to be much higher as compared to chimpanzee and macaque brains, but GLUT4 expression is higher in chimpanzee skeletal muscle than in human and macaque muscle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pfefferle et al. 2011

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    Premisecitation
    § Costly human brain: evolutionary implications

    Some studies connected the possibility of having such a costly brain with the relative reduction of gut or skeletal muscles in volume or with the decrease of energy spent on locomotive tasks.

    “Some studies connected the possibility of having such a costly brain with the relative reduction of gut (Aiello and Wheeler 1995) or skeletal muscles (Leonard et al. 2003) in volume or with the decrease of energy spent on locomotive tasks (Navarrete et al. 2011).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Aiello and Wheeler 1995

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    • cites Leonard et al. 2003

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    • cites Navarrete et al. 2011

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  • May combine two claims.

    Interpretationreasoning
    § The importance of maintaining brain energy homeostasis

    The existence of many alternative energy sources to fuel the brain as well as the pathological consequences of disturbed regional/global brain metabolism and energetics highlight the importance of maintaining brain energy homeostasis.

    “The existence of many alternative energy sources to fuel the brain as well as the pathological consequences of disturbed regional/global brain metabolism and energetics highlight the importance of maintaining brain energy homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Costly human brain: evolutionary implications

    The expression of the active creatine transporter SLC6A8 and the brain-type cytosolic creatine kinase are higher in humans than in chimpanzees and rhesus macaques in cerebral cortex and cerebellum, but not in skeletal muscles.

    “The expression of the active creatine transporter SLC6A8 and the brain-type cytosolic creatine kinase are higher in humans than in chimpanzees and rhesus macaques in cerebral cortex and cerebellum, but not in skeletal muscles (Pfefferle et al. 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pfefferle et al. 2011

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139 of 139

  • The paper relies on this without support.

    K+ is released at nodes of Ranvier during AP propagation, at serotonergic synapses, or at the cholinergic neuromuscular junction.

    “as K + is released not only by the postsynaptic terminal during glutamatergic neurotransmission but also at nodes of Ranvier during AP propagation, at serotonergic synapses, or at the cholinergic neuromuscular junction.”

  • The paper relies on this without support.

    Uptake of extracellular glutamate is expensive as astrocytes utilize one ATP for the transfer of one glutamate.

    “Uptake of extracellular glutamate is an expensive process as astrocytes utilize one ATP for the transfer of one glutamate.”

  • The authors state this as an assumption.

    Lactate secreted by astrocytes through MCT1 and MCT4 is transported by MCT2 into neurons, where it can be converted to pyruvate.

    “Hence, lactate secreted by astrocytes through MCT1 and MCT4 is assumed to be transported by MCT2 into neurons, where it can be converted to pyruvate (Fig. 2).”

  • The paper relies on this without support.

    Energy homeostasis is essential in maintaining a healthy state of the brain.

    “Energy homeostasis is essential in maintaining a healthy state of the brain.”

  • The paper relies on this without support.

    Microglia and macrophages within the CNS have a high energetic demand to function as they monitor for abnormalities and make connections with neurons.

    “Microglia and macrophages within the CNS have a high energetic demand to function as they monitor for abnormalities and make connections with neurons.”

  • The paper relies on this without support.

    The three major energy substrates in microglia are glucose, fatty acids, and glutamine.

    “The three major energy substrates in microglia are glucose, fatty acids, and glutamine.”

  • The paper relies on this without support.

    Disrupted energy homeostasis may either be a cause or an effect of a disease or a disease-like condition (i.e., unhealthy aging).

    “Disrupted energy homeostasis may either be a cause or an effect of a disease or a disease-like condition (i.e., unhealthy aging).”

  • The paper relies on this without support.

    Metabolic changes not only contribute to the pathology of neurodegenerative diseases, traumatic brain injury, or stroke but also cause neurological symptoms of diabetes mellitus, and accompany normal aging.

    “Metabolic changes not only contribute to the pathology of neurodegenerative diseases, traumatic brain injury, or stroke but also cause neurological symptoms of diabetes mellitus, and accompany normal aging.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the brain, ATP is required for neurotransmitter synthesis, protein turnover, neurotransmission, transport, and maintenance of ion gradients.

    “In the brain, ATP is required for neurotransmitter synthesis, protein turnover, neurotransmission, transport, and maintenance of ion gradients [119].”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [119]

    The sections “Why does the brain have high energy expenditure?” and “Presynaptic terminals” describe ATP use in synaptic transmission, transport, and maintaining ion gradients; “Non-signaling (‘housekeeping’) processes” also discusses energy use in protein metabolism. The copy describes enzymatic processing and vesicle loading of neurotransmitters, but does not clearly state that ATP is required for neurotransmitter synthesis specifically. Page numbers were not available in the indexed passages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • When glucose availability is reduced, the brain can use alternative energy substrates such as lactate, medium-chain triglycerides and ketone bodies.

    “However, when glucose availability is reduced, the brain can use alternative energy substrates such as lactate, medium-chain triglycerides and ketone bodies [30].”

    From Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence (2020) · cites this paper as [30]

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 2

  1. 10.1242/jeb.02208 · DOI
  2. Silva G. S. S., 2017, Amyloid‐β oligomers transiently inhibit AMP‐activated kinase and cause metabolic defects in hippocampal neurons, J. Biol. Chem., 116, 753525

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Related

Authors
Bordone, M. P., Salman, M. M., Titus, H. E., Amini, E., Andersen, J. V., Chakraborti, B., Diuba, A. V., Dubouskaya, T. G., Ehrke, E., Espindola de Freitas, A., Braga de Freitas, G., Gonçalves, R. A., Gupta, D., Gupta, R., Ha, S. R., Hemming, I. A., Jaggar, M., Jakobsen, E., Kumari, P., Lakkappa, N., Marsh, A. P. L., Mitlöhner, J., Ogawa, Y., Paidi, R. K., Ribeiro, F. C., Salamian, A., Saleem, S., Sharma, S., Silva, J. M., Singh, S., Sulakhiya, K., Tefera, T. W., Vafadari, B., Yadav, A., Yamazaki, R., & Seidenbecher, C. I.
Affiliations
  • Universidad de Buenos Aires (AR)
  • Boston Children's Hospital (US)
  • Northwestern University (US)
  • University Kebangsaan Malaysia Medical Centre (MY)
  • University of Copenhagen (DK)
  • Manovikas Kendra Rehabilitation and Research Institute (IN)
  • Lomonosov Moscow State University (RU)
  • National Academy of Sciences of Belarus (BY)
  • University of Bremen (DE)
  • Neurobiology Section Biological Sciences Division University of California San Diego, La Jolla California USA
  • Institute of Medical Biochemistry Federal University of Rio de Janeiro Rio de Janeiro Brazil
  • Queen's University (CA)
  • Birla Institute of Technology and Science, Pilani (IN)
  • Indian Institute of Toxicology Research (IN)
  • Baylor College of Medicine (US)
  • The University of Western Australia (AU)
  • Tata Institute of Fundamental Research (IN)
  • Defence Research and Development Organisation (IN)
  • JSS College of Pharmacy (IN)
  • Royal Children's Hospital (AU)
  • Leibniz Institute for Neurobiology (DE)
  • Jikei University School of Medicine (JP)
  • Indian Institute of Chemical Biology (IN)
  • Universidade Federal do Rio de Janeiro (BR)
  • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
  • University of Minho (PT)
  • Indira Gandhi National Tribal University (IN)
  • The University of Queensland (AU)
  • Technical University of Munich (DE)
  • Tokyo University of Pharmacy and Life Sciences (JP)
  • Center for Behavioral Brain Sciences (DE)
Corresponding author
Seidenbecher, Constanze I.
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2019-09-10
Volume
151
Issue
2
Pages
139-165
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.14829
OpenAlex
W2964281414
Semantic Scholar
d9e216030a3b4d892a19f367b66743386c20611d
Cited by
205
References
331
Citations by year
2026: 14 · 2025: 31 · 2024: 16 · 2023: 25 · 2022: 33 · 2021: 53 · 2020: 29 · 2019: 4
FWCI
3.96
Type
journal article
Language
en
Update notices
correction (2020-03-09)
Open access
Licence
Locations
  • Journal of Neurochemistry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • CONICET Digital (CONICET) (submittedVersion, cc-by-nc-nd)
  • OPUS (Augsburg University) (submittedVersion, cc-by-nc-nd)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by-nc-nd)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
Funders
  • Deutsche Forschungsgemeinschaft (RTG2413, SFB 779)
  • Bundesministerium für Bildung und Forschung
  • Lundbeckfonden (R249-2017-109)
  • International Society for Neurochemistry
  • European Social Fund (ZS/2016/08/80645)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
brain energy metabolism, mitochondrial quality control, neurotransmission, synaptic plasticity, glucose metabolism, glutamate, lactate, ketone bodies, medium-chain fatty acids, astrocytes, pericytes, microglia, energy homeostasis, central nervous system disorders
MeSH terms
Animals, Astrocytes, Brain, Congresses as Topic, Energy Metabolism, Humans, Neurochemistry, Neuroglia, Neurons, Students

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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