Energy Metabolism in Astrocytes and Neurons

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Energy Metabolism in Astrocytes and Neurons

• Yufeng Zhang

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Fuel selection

• The energy requirements of the brain are very
  high
• Lipids contain more energy compare to other
  substrate
• Other organs use lipids as fuel
• Fatty acid metabolism has a role in
  neurodevelopment, neurotransmission, and repair
  processes

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Reasons for low FFA oxidation

• (i) a slow passage of fatty acids across the
  bloodbrain barrier (BBB)
• (ii) a low enzymatic capacity for the fatty acid
  degradation
• (iii) side effects of long-chain fatty acids in
  the mitochondrial ATP synthesis

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BBB Permeability

• In situ perfusion technique demonstrating that
  long-chain NEFA are rapidly transported through
  the BBB to a large portion and with similar rates
• passive transport or alternatively
• protein-mediated diffusion

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FFA in mitochondria

• Eightfold lower than that of heart mitochondria
  under comparable conditions
• High oxygen consumption with pyruvate or
  glutamate as hydrogen donors, as compared with
  heart and skeletal muscle mitochondria
• Low-level oxidation of long-chain fatty
  attributed to
• low translocation rate
• low enzymatic capacity of the ß-oxidation pathway

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Harmful side effect
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Other reasons

• Oxidation of Fatty Acids Increases the Tendency
  of Neural Tissue to Become Hypoxic
• Increases the Risk of enhanced Oxidative Stress
• Fatty Acid Oxidation is too Slow for Matching the
  ATP Requirements

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Astrocyte-Neuron Metabolic Cooperation

• Blood delivery increases with metabolic demand,
• CBF and CMRglc increase more than oxygen
  utilization, and
• Both oxidative and nonoxidative processes are
  involved to meet the increased metabolic
  requirements

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Cytoarchitectural organization of brain

• Astrocytes have emerged as active players in
  brain energy delivery, production, utilization,
  and storage
• Astrocytes possess unique cytoarchitectural and
  phenotypic features that ideally position them to
  sense their surroundings and dynamically respond
  to changes in their microenvironment

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Regulationof Cerebral Blood Flow

• Astrocytes play a key role in neurovascular
  coupling
• Coupling between neuronal activity and increased
  CBF (AKA hyperemia)
• Essential contributors to both vasoconstriction
  and vasodilation.

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1) Increased astrocytic Ca concentrationsactiva
tion of glycolysis--- elevation of extracellular
lactate --- dilation. 2) More oxygen
---astrocytic Ca2 signals would induce a
constricting tone ---keeping CBF at an
appropriate lower level
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Metabolic Specialization of Neurons and Glia

• Brain dependent upon the uninterrupted supply of
  energy substrates from the circulation.
• In addition to glucose, including lactate,
  pyruvate, glutamate, and glutamine can also be
  energy substrate
• Lactate used to be considered a metabolic dead end

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Metabolic Profile

• Neurons sustain a high rate of oxidative
  metabolism compared to glial cells.
• 6-phosphofructose-2-kinase/fructose-2,6-
• bisphosphatase-3 (Pfkfb3) is virtually absent
  in neurons
• a potent activator of the glycolytic enzyme
  phosphofructokinase-1 (PFK)
• The use of lactate high ATP, thereby sparing
  glucose for the PPP.
• Astrocytes take up glucose and characteristically
  present a high glycolytic rate, end with lactate

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NeurotransmitterRecycling and Anaplerosis

• Astrocytes can rapidly remove neurotransmitters
  released into the synaptic cleft
• Glutamate overstimulation of glutamate receptors
  is highly toxic to neurons
• Astrocytes also play an important role in
  transferring this neurotransmitter back to neurons

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Astrocyte-Neuron Lactate Shuttle

• Amount of glucose that astrocytes take up is
  higher to their energy requirements
• (1) neuronal activity increases extracellular
  glutamate which is avidly taken up via a
  Na-dependent mechanism
• (2) increase in Na activates the Na/K ATPase
  thereby increasing ATP consumption
• (3) leads to a large increase in the production
  of lactate in the extracellular space
• (4) lactate can be used as an energy substrate
  for neurons

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Astrocytic Glycogen Metabolism

• Glycogen is the largest energy reserve of the
  brain
• Glycogen has been found to be almost exclusively
  localized in astrocytes

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Prior to inhibitory avoidance training, rats
received intrahippocampal injections of (DAB, a
potent inhibitor of glycogen phosphorylase),
lactate, or antisense oligodeoxynucleotides, as
indicated. Short-term memory (STM) was assessed 1
hr later (experiment 1), while long-term memory
(LTM) formation was assessed after 1 and 7 days
(experiments 27).
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Astrocytic glycogen is more than a simple
emergency reserve, and plays an important and
active role in complex brain physiological
functions, in particular through an
astrocyte-to-neuron transfer of energy
metabolites in the form of lactate.
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Defense against Oxidative Stress

• The brain is particularly susceptible to
  oxidative damage
• high rate of oxidative energy metabolism
• high unsaturated fatty acids content
• Relatively low intrinsic antioxidant capacity
• Astrocytes have higher levels of various
  antioxidant molecules
• Neurons are dependent upon the high antioxidant
  potential of astrocytes

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GSHthe most abundant antioxidant molecule in the
brain neurons are highly dependent on astrocytes
for the supply of the precursor amino acids
necessary for their own GSH synthesis
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Metabolic Plasticity in Astrocytes

• Astrocytes have a greater metabolic plasticity
  than neurons
• Any significant alteration of astrocytic pathways
  caused by pathological stimuli could potentially
  contribute to neuronal dysfunction
• Enhancing astrocytic functions may represent
  therapeutic avenues for neurodegenerative disease

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Neuronal Excitability

• Glucose-sensing neurons increase their firing
  rate in response to elevation of central glucose
  levels, ultimately resulting in decreased blood
  glucose and insulin levels and the suppression of
  hepatic gluconeogenesis
• Orexin neurons also function as lactate sensors
• Salt-intake behavior is also influenced by
  extracellular astrocyte-derived lactate

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What extent neurons are fed directly by glucose
or by lactate?

• Method
• Mixed culture of neuronal and glial cells
• Probes 2-NBDG and 6-NBDG
• Optical measurements
• Protein extraction and Immunoblot

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Conclusion

• Neural cells dont use Fatty Acid as fuel, which
  helps to protect neural cells against enhanced
  oxidative stress
• Neuroenergetics has evolved from a neurocentric
  view into a more integrated one in which
  complementarities and cooperativities between
  astrocytes and neurons.
• lactate shuttling from astrocytes to neurons

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Thank you