Metabolism of the Nervous System

The nervous system consists of various cell types. The most abundant cell in the

nervous system is the glial cell, which consists of astrocytes and

oligodendrocytes in the central nervous system (CNS), and Schwann cells in

the peripheral nervous system (PNS). These cells provide support for the

neurons and synthesize the protective myelin sheath that surrounds the axons

emanating from the neurons. Microglial cells in the nervous system act as

immune cells, destroying and ingesting foreign organisms that enter the nervous

system. The interface between the brain parenchyma and the cerebrospinal

fluid (CSF) compartment is formed by the ependymal cells, which line the

cavities of the brain and spinal cord. These cells use their cilia to allow for the

circulation of the CSF, which bathes the cells of the CNS.

The cells of the brain are separated from free contact with the rest of the

body by the blood–brain barrier. The capillaries of the brain exhibit features,

such as tight endothelial cell junctions, that restrict their permeability to

metabolites in the blood. This protects the brain from compounds that might be

toxic or otherwise interfere with nerve impulse transmission. It also affects the

entry of precursors for brain metabolic pathways such as fuel metabolism and

neurotransmitter synthesis.

Neurotransmitters can be divided structurally into two categories: small

nitrogen-containing neurotransmitters and neuropeptides. The small

nitrogen-containing neurotransmitters are generally synthesized in the

presynaptic terminal from amino acids and intermediates of glycolysis and the

tricarboxylic acid (TCA) cycle. They are retained in storage vesicles until the

neuron is depolarized. The catecholamine neurotransmitters (dopamine,

norepinephrine, and epinephrine) are derived from tyrosine. Serotonin is

synthesized from tryptophan. Acetylcholine is synthesized from choline, which

can be supplied from the diet or is synthesized and stored as part of

phosphatidylcholine. Glutamate and its neurotransmitter derivative, γ-

aminobutyric acid (GABA), are derived from α-ketoglutarate in the TCA

cycle. Glycine is synthesized in the brain from serine. The synthesis of the
neurotransmitters is regulated to correspond to the rate of depolarization of the

individual neurons. A large number of cofactors are required for the synthesis of

neurotransmitters, and deficiencies of pyridoxal phosphate, thiamin

pyrophosphate, and vitamin B12 result in a variety of neurologic dysfunctions.

Brain metabolism has a high requirement for glucose and oxygen.

Deficiencies of either (hypoglycemia or hypoxia) affect brain function because

they influence adenosine triphosphate (ATP) production and the supply of

precursors for neurotransmitter synthesis. Ischemia elicits a condition in which

increased calcium levels, swelling, glutamate excitotoxicity, and nitric oxide

generation affect brain function and can lead to a stroke. The generation of free

radicals and abnormalities in nitric oxide production are important players in the

pathogenesis of a variety of neurodegenerative diseases.

Because of the restrictions posed by the blood–brain barrier to the entry of a

variety of substances into the CNS, the brain generally synthesizes and degrades

its own lipids. Essential fatty acids can enter the brain, but the more common

fatty acids do not. The turnover of lipids at the synaptic membrane is very rapid,

and the neuron must replace those lipids lost during exocytosis. The glial cells

produce the myelin sheath, which is composed primarily of lipids. These lipids

are of a different composition than those of the neuronal cells. Because there is

considerable lipid synthesis and turnover in the brain, this organ is sensitive to

disorders of peroxisomal function (Refsum disease; interference in very-longchain

fatty acid oxidation and α-oxidation) and lysosomal diseases

(mucopolysaccharidoses; inability to degrade complex lipids and glycolipids).

I. Cell Types of the Nervous System

The nervous system consists of neurons, the cells that transmit signals, and

supporting cells, the neuroglia. The neuroglia consist of oligodendrocytes and

astrocytes (known collectively as glial cells), microglial cells, ependymal cells,

and Schwann cells. The neuroglia are designed to support and sustain the

neurons and do so by surrounding neurons and holding them in place, supplying

nutrients and oxygen to the neurons, insulating neurons so their electrical signals

are more rapidly propagated, and cleaning up any debris that enters the nervous
system. The CNS consists of the brain and spinal cord. This system integrates all

signals emanating from the PNS. The PNS is composed of all neurons that lie

outside the CNS.

A. Neurons

Neurons consist of a cell body (soma) from which long (axons) and short

(dendrites) extensions protrude. Dendrites receive information from the axons of

other neurons, whereas the axons transmit information to other neurons. The

axon–dendrite connection is known as a synapse (Fig. 46.1). Most neurons

contain multiple dendrites, each of which can receive signals from multiple

axons. This configuration allows a single neuron to integrate information from

multiple sources. Although neurons also contain just one axon, most axons

branch extensively and distribute information to multiple targets (divergence).

The neurons transmit signals by changes in the electrical potential across their

membrane. Signaling across a synapse requires the release of neurotransmitters

that, when bound to their specific receptors, initiate an electrical signal in the

receiving or target cell. Neurons are terminally differentiated cells and, as such,

have little capability for division. As a result, injured neurons have a limited

capacity to repair themselves and frequently undergo apoptosis (programmed

cell death) when damaged.

B. Neuroglial Cells

1. Astrocytes
The astrocytes are found in the CNS and are star-shaped cells that provide

physical and nutritional support for neurons. During development of the CNS,

the astrocytes guide neuronal migration to their final adult position and form a

matrix that keeps neurons in place. These cells serve several functions, including

phagocytosing debris left behind by cells, providing lactate (from glucose

metabolism) as a carbon source for the neurons, and controlling the brain

extracellular ionic environment. Astrocytes help to regulate the content of the

extracellular fluid (ECF) by taking up, processing, and metabolizing nutrients

and waste products.

2. Oligodendrocytes

Oligodendrocytes provide the myelin sheath that surrounds the axon, acting as

“insulation” for many of the neurons in the CNS. The myelin sheath is the lipid–

protein covering of the axons (see Section V.B for a description of the

composition and synthesis of the myelin sheath). Oligodendrocytes can form

myelin sheaths around multiple neurons in the CNS by sending out processes

that bind to the axons on target neurons. The speed with which a neuron

conducts its electric signal (action potential) is directly proportional to the

degree of myelination. Oligodendrocytes, along with the astrocytes, form a

supporting matrix for the neurons. Oligodendrocytes have a limited capacity for

mitosis and, if damaged, do not replicate. If this occurs, demyelination of the

axons may occur, resulting in abnormalities in signal conduction along that axon

(see “Biochemical Comments”).

3. Schwann Cells

Schwann cells are the supporting cells of the PNS. Like oligodendrocytes,

Schwann cells form myelin sheaths around the axons, but unlike the

oligodendrocytes, Schwann cells myelinate only one axon; they also clean up

cellular debris in the PNS. In addition, Schwann cells provide a means for

peripheral axons to regenerate if damaged. There is a synergistic interaction

among the Schwann cells, secreted growth factors, and the axon that allows

damaged axons to reconnect to the appropriate target axon.

4. Microglial Cells
The microglial cells are the smallest glial cells in the nervous system. They serve

as immunologically responsive cells that function similarly to the action of

macrophages in the circulation. Microglial cells destroy invading

microorganisms and phagocytose cellular debris.

5. Ependymal Cells

The ependymal cells are ciliated cells that line the cavities (ventricles) of the

CNS and the spinal cord. In some areas of the brain, the ependymal cells are

functionally specialized to elaborate and secrete CSF into the ventricular system.

The beating of the ependymal cilia allows for efficient circulation of the CSF

throughout the CNS. The CSF acts as both a shock absorber protecting the CNS

from mechanical trauma and as a system for the removal of metabolic wastes.

The CSF can be aspirated from the spinal canal and analyzed to determine

whether disorders of CNS function, with their characteristic CSF changes, are

present.

For many years, it had been believed that damaged neurons in the CNS could

not regenerate because it was thought that there are no pluripotent stem cells

(cells that can differentiate into various cell types found in the CNS) in the CNS.

However, recent data suggest that cells found within the ependymal layer can act

as neural stem cells, which under appropriate stimulation can regenerate cells

within the nervous system. Such a finding opens up a large number of potential

treatments for diseases that alter neuronal cell function.

II. The Blood–Brain Barrier

A. Capillary Structure

In the capillary beds of most organs, rapid passage of molecules occurs from the

blood through the endothelial wall of the capillaries into the interstitial fluid.

Thus, the composition of interstitial fluid resembles that of blood, and specific

receptors or transporters in the plasma membrane of the cells being bathed by

the interstitial fluid may interact directly with amino acids, hormones, or other

compounds from the blood. In the brain, transcapillary movement of substrates

in the peripheral circulation into the brain is highly restricted by the blood–brain

barrier. This barrier limits the accessibility of bloodborne toxins and other
potentially harmful compounds to the neurons of the CNS.

The blood–brain barrier begins with the endothelial cells that form the inner

lining of the vessels supplying blood to the CNS (Fig. 46.2). Unlike the

endothelial cells of other organs, these cells are joined by tight junctions that do

not permit the movement of polar molecules from the blood into the interstitial

fluid bathing the neurons. They also lack mechanisms for transendothelial

transport that are present in other capillaries of the body. These mechanisms

include fenestrations (“windows” or pores that span the endothelial lining and

permit the rapid movement of molecules across membranes) or transpinocytosis

(vesicular transport from one side of the endothelial cell to another).

The endothelial cells serve actively, as well as passively, to protect the brain.

Because they contain a variety of drug-metabolizing enzyme systems similar to

the drug-metabolizing enzymes found in the liver, the endothelial cells can

metabolize neurotransmitters and toxic chemicals and, therefore, form an

enzymatic barrier to entry of these potentially harmful substances into the brain.

They actively pump hydrophobic molecules that diffuse into endothelial cells

back into the blood (especially xenobiotics) with P-glycoproteins, which act as
transmembranous, ATP-dependent efflux pumps. Although lipophilic substances,

water, oxygen, and carbon dioxide can readily cross the blood–brain barrier by

passive diffusion, other molecules depend on specific transport systems.

Differential transporters on the luminal and abluminal endothelial membranes

can transport compounds into, as well as out of, the brain.

Further protection against the free entry of bloodborne compounds into the

CNS is provided by a continuous collagen-containing basement membrane that

completely surrounds the capillaries. The basement membrane appears to be

surrounded by the foot processes of astrocytes. Thus, compounds must pass

through endothelial cell membranes, the enzymatic barrier in the endothelial

cells, the basement membrane, and possibly additional cellular barriers formed

by the astrocytes to reach the neurons in the brain.

B. Transport through the Blood–Brain Barrier

Many nonpolar substances, such as drugs and inert gases, probably diffuse

through the endothelial cell membranes. A large number of other compounds are

transported through the endothelial capillaries by facilitative transport, whereas

others, such as nonessential fatty acids, cannot cross the blood–brain barrier.

Essential fatty acids, however, are transported across the barrier.

1. Fuels

Glucose, which is the principal fuel of the brain, is transported through both

endothelial membranes by facilitated diffusion via the GLUT 1 transporter (see

Fig. 21.9). GLUT 3 transporters present on the neurons then allow the neurons to

transport the glucose from the ECF. Glial cells express GLUT 1 transporters.

Although the rate of glucose transport into the ECF normally exceeds the rate

required for energy metabolism by the brain, glucose transport may become ratelimiting

as blood glucose levels fall below the normal range. Thus, individuals

begin to experience hypoglycemic symptoms at glucose levels of approximately

60 mg/dL, as the glucose levels are reduced to the Km, or below the Km values of

the GLUT 1 transporters in the endothelial cells of the barrier.

Several disorders of glucose transport across the blood–brain

transporter protein type 1 (GLUT 1) deficiency syndrome. In this

disorder, GLUT 1 transporters are impaired, which results in a low

glucose concentration in the CSF (a condition known as

hypoglycorrhachia). A diagnostic indication of this disorder is that in the

presence of normal blood glucose levels the ratio of CSF glucose to

blood glucose levels is <0.4. Clinical features are variable but include

seizures, developmental delay, and a complex motor disorder. These

symptoms are the result of inadequate glucose levels in the brain. The

disorder can be treated by prescribing a ketogenic diet (high-fat, lowcarbohydrate).

This will force the patient to produce ketone bodies,

which are easily transported into the CNS and can partially spare the

brain’s requirement for glucose as an energy source.

Monocarboxylic acids, including L-lactate, acetate, pyruvate, and the ketone

bodies acetoacetate and β-hydroxybutyrate, are transported by a separate

stereospecific system that is slower than the transport system for glucose. During

starvation, when the level of ketone bodies in the blood is elevated, this

transporter is upregulated. Ketone bodies are important fuels for the brain of

both adults and neonates during prolonged starvation (>46 hours).

2. Amino Acids and Vitamins

Large neutral amino acids (LNAAs) (such as phenylalanine, leucine, tyrosine,

isoleucine, valine, tryptophan, methionine, and histidine) enter the CSF rapidly

via a single amino acid transporter (L [leucine preferring] system amino acid

transporter). Many of these compounds are essential in the diet and must be

imported for protein synthesis or as precursors of neurotransmitters. Because a

single transporter is involved, these amino acids compete with each other for

transport into the brain.

The entry of small neutral amino acids, such as alanine, glycine, proline, and

GABA, is markedly restricted because their influx could dramatically change the

content of neurotransmitters (see Section III). They are synthesized in the brain,

and some are transported out of the CNS and into the blood via the A (alaninepreferring)
system carrier. Vitamins have specific transporters through the

blood–brain barrier, just as they do in most tissues.

The finding that the LNAAs have a common carrier system across

the blood–brain barrier suggests that if one amino acid is in excess,

it can, by competitive inhibition, result in lower transport of the other

amino acids. This suggests that the mental retardation that results from

untreated phenylketonuria (PKU) and maple syrup urine disease (see

Chapter 37) may be attributable to the high levels of either phenylalanine

or branched-chain amino acids in the blood. These high levels

overwhelm the LNAA carrier so that excessive levels of the damaging

amino acid enter the CNS. In support of this theory is the finding that

treatment of patients with PKU with large doses of LNAAs that lack

phenylalanine resulted in a decrease of phenylalanine levels in the CSF

and brain, with an improvement in the patients’ cognitive functions as

well.

3. Receptor-Mediated Transcytosis

Certain proteins, such as insulin, transferrin, and insulin-like growth factors,

cross the blood–brain barrier by receptor-mediated transcytosis. Once the protein

binds to its membrane receptor, the membrane containing the receptor–protein

complex is endocytosed into the endothelial cell to form a vesicle. It is released

on the other side of the endothelial cell. Absorption-mediated transcytosis also

can occur. This differs from receptor-mediated transcytosis in that the protein

binds nonspecifically to the membrane and not to a distinct receptor.

IV. Metabolic Encephalopathies and Neuropathies

The brain has an absolute dependence on the blood for its supply of glucose and

oxygen. It uses approximately 20% of the oxygen supply of the body. During the

developmental period and during prolonged fasting, ketone bodies can be used

as a fuel, but they cannot totally substitute for glucose. Glucose is converted to

pyruvate in glycolysis, and the pyruvate is oxidized in the TCA cycle. Anaerobic

glycolysis, with a yield of two molecules of ATP per molecule of glucose, cannot

sustain the ATP requirement of the brain, which can be provided only by the
complete oxidation of glucose to CO2, which yields approximately 32

ATP/glucose. However, during periods of mild hypoglycemia or mild hypoxia,

decreased neurotransmitter synthesis contributes as much, if not more, to the

development of symptoms, as does an absolute deficiency of ATP for energy

needs.

A. Hypoglycemic Encephalopathy

Hypoglycemia is sometimes encountered in medical conditions such as

malignancies that produce insulin or insulinlike growth factors, or chronic

alcoholism. Early clinical signs in hypoglycemia reflect the appearance of

physiologic protective mechanisms initiated by hypothalamic sensory nuclei,

such as sweating, palpitations, anxiety, and hunger. If these symptoms are

ignored, they proceed to a more serious CNS disorder, progressing through

confusion and lethargy to seizures and, eventually, coma. Prolonged

hypoglycemia can lead to irreversible brain damage.

During the progression of hypoglycemic encephalopathy, as blood glucose

falls to <2.5 mM (45 mg/dL), the brain attempts to use internal substrates such as

glutamate and TCA cycle intermediates as fuels. Because the pool size of these

substrates is quite small, they are quickly depleted. If blood glucose levels

continue to fall to <1 mM (18 mg/dL), ATP levels become depleted.

As the blood glucose level drops from 2.5 to 2.0 mM (45 to 36 mg/dL,

before electroencephalographic [EEG] changes are observed), the symptoms

appear to arise from decreased synthesis of neurotransmitters in particular

regions of the brain rather than a global energy deficit. The oxidation of glucose

in glycolysis provides 3-phosphoglycerate, a precursor for the neurotransmitter

glycine. Pyruvate entry into the mitochondria and conversion to acetyl-CoA can

generate α-ketoglutarate (for glutamate and GABA synthesis) and oxaloacetate,

for the synthesis of the neurotransmitter aspartate. A lack of glucose could

disrupt the synthesis of these neurotransmitters.

As hypoglycemia progresses below 1 mM (18 mg/dL) and high-energy

phosphate levels are depleted, the EEG becomes isoelectric, and neuronal cell

death ensues. As is the case in some other metabolic encephalopathies, cell death
is not global in distribution; rather, certain brain structures—in particular,

hippocampal and cortical structures—are selectively vulnerable to hypoglycemic

insult. Pathophysiologic mechanisms responsible for neuronal cell death in

hypoglycemia include the involvement of glutamate excitotoxicity. Glutamate

excitotoxicity occurs when the cellular energy reserves are depleted. The failure

of the energy-dependent reuptake pumps results in a buildup of glutamate in the

synaptic cleft and overstimulation of the postsynaptic glutamate receptors. The

prolonged glutamate receptor activation leads to prolonged opening of the

receptor ion channel and the influx of lethal amounts of Ca2+ ion, which can

activate cytotoxic intracellular pathways in the postsynaptic neuron.

B. Hypoxic Encephalopathy

Experimental studies with human volunteers show that cerebral energy

metabolism remains normal when mild to moderate hypoxia (partial pressure of

oxygen [PaO2] = 25 to 40 mm Hg) results in severe cognitive dysfunction. The

diminished cognitive function is believed to result from impaired

neurotransmitter synthesis. In mild hypoxia, cerebral blood flow increases to

maintain oxygen delivery to the brain. In addition, anaerobic glycolysis is

accelerated, resulting in maintenance of ATP levels. This occurs, however, at the

expense of an increase of lactate production and a fall of pH. Acute hypoxia

(PaO2 ≤20 mm Hg) generally results in a coma.

Hypoxia can result from insufficient oxygen reaching the blood (e.g., at high

altitudes), severe anemia (e.g., iron deficiency), or a direct insult to the oxygenusing

capacity of the brain (e.g., cyanide poisoning). All forms of hypoxia result

in diminished neurotransmitter synthesis. Inhibition of pyruvate dehydrogenase

diminishes acetylcholine synthesis, which is acutely sensitive to hypoxia.

Glutamate and GABA synthesis, which depend on a functioning TCA cycle, are

decreased as a result of elevated reduced nicotinamide adenine dinucleotide

(NADH) levels, which inhibit TCA-cycle enzymes. NADH levels are increased

when oxygen is unavailable to accept electrons from the electron-transport chain

and NADH cannot be readily converted back into NAD+. Even the synthesis of

catecholamine neurotransmitters may be decreased because the hydroxylase

C. Relationship between Glutamate Synthesis and the Anaplerotic Pathways

of Pyruvate Carboxylase and Methylmalonyl Coenzyme A Mutase

Synthesis of glutamate removes a-ketoglutarate from the TCA cycle, thereby

decreasing the regeneration of oxaloacetate in the TCA cycle. Because

oxaloacetate is necessary for the oxidation of acetyl-CoA, oxaloacetate must be

replaced by anaplerotic reactions. There are two major types of anaplerotic

reactions: (1) pyruvate carboxylase and (2) the degradative pathway of the

branched-chain amino acids valine and isoleucine, which contribute succinyl

coenzyme A (succinyl-CoA) to the TCA cycle. This pathway uses vitamin B12

(but not folate) in the reaction catalyzed by methylmalonyl coenzyme A

(methylmalonyl-CoA) mutase.

V. Lipid Synthesis in the Brain and Peripheral Nervous System

Several features of lipid synthesis and degradation in the nervous system

distinguish it from most other tissues. The first is that the portion of the neuronal

cell membrane involved in synaptic transmission has a unique role and a unique

composition. At the presynaptic terminal, the lipid composition changes rapidly

as storage vesicles containing the neurotransmitter fuse with the cell membrane

and release their contents. Portions of the membrane are also lost as endocytotic

vesicles. On the postsynaptic terminal, the membrane contains the receptors for

the neurotransmitter as well as a high concentration of membrane signaling

components, such as phosphatidylinositol. A second important feature of brain

lipid metabolism is that the blood–brain barrier restricts the entry of nonessential

fatty acids, such as palmitate, that are released from adipose tissue or present in

the diet. Conversely, essential fatty acids are taken up by the brain. Because of

these considerations, the brain is constantly synthesizing those lipids

(cholesterol, fatty acids, glycosphingolipids, and phospholipids), which it needs

for various neurologic functions. Neuronal signaling also requires that

nonneuronal glial cells synthesize myelin, a multilayered membrane that

surrounds the axons of many neurons. Myelin is lipid-rich and has a different

lipid composition than the neuronal membranes. The white matter in the brain
contains significantly more myelin than the gray matter; it is the presence of

myelin sheaths that is responsible for the characteristic color differences that

exist between the two types of brain tissue.

A. Brain Lipid Synthesis and Oxidation

Because the blood–brain barrier significantly inhibits the entry of certain fatty

acids and lipids into the CNS, virtually all lipids found there must be synthesized

within the CNS. The exceptions are the essential fatty acids (linoleic and

linolenic acid), which do enter the brain, where they are elongated or further

desaturated. The uptake of fatty acids into the CNS is insufficient to meet the

energy demands of the CNS—hence, the requirement for aerobic glucose

metabolism. Thus, cholesterol, glycerol, sphingolipids, glycosphingolipids, and

cerebrosides are all synthesized using pathways discussed previously in this text.

Of particular note is that very-long-chain fatty acids are synthesized in the brain,

where they play a major role in myelin formation.

Oxidation and turnover of brain lipids occurs as described previously (see

Chapter 30). Peroxisomal fatty acid oxidation is important in the brain because

the brain contains very-long-chain fatty acids and phytanic acid (from the diet),

both of which are oxidized in the peroxisomes by α-oxidation. Thus, disorders

that affect peroxisome biogenesis (such as Refsum disease) severely affect brain

cells because of the inability to metabolize both branched-chain and very-longchain

fatty acids. If there is a disorder in which the degradation of

glycosphingolipids or mucopolysaccharides is impaired, lysosomes in brain cells

become engorged with partially digested glycolipids, leading to varying degrees

of neurologic dysfunction.

B. Myelin Synthesis

A rapid rate of nerve conduction in the peripheral and central motor nerves

depends on the formation of myelin, a multilayered lipid and protein structure

that is formed from the plasma membrane of glial cells. In the PNS, the Schwann

cell is responsible for myelinating one portion of an axon of one nerve cell. The

Schwann cell does this by wrapping itself around the axon multiple times so that

a multilayered sheath of membrane surrounds the axon. In the CNS, the

oligodendrocytes can myelinate portions of numerous axons (up to 40), and do

so by extending a thin process that wraps around the axon multiple times. Thus,

CNS axons are surrounded only by the membranes of oligodendrocytes, whereas

axons in the PNS are surrounded by the entire Schwann cell. A generalized view

of myelination is depicted in Figure 46.13. To maintain the myelin structure, the

oligodendrocyte synthesizes four times its own weight in lipids per day.

1. Myelin Lipids

As the plasma membrane of the glial cell is converted into myelin, the lipid

composition of the brain changes (Table 46.2). The lipid-to-protein ratio is

greatly increased, as is the content of sphingolipids. The myelin is a tightly

packed structure, and there are significant hydrophobic interactions between the

lipids and proteins to allow this to occur. Cerebrosides constitute approximately

16% of total myelin lipid and are almost completely absent from other cell-type

membrane lipids. The predominant cerebroside, galactosylcerebroside, has a

single sugar attached to the hydroxyl group of the sphingosine. In contrast,

sphingomyelin, which one might guess is the predominant lipid of myelin, is

present in roughly the same low concentration in all membranes.

Galactocerebrosides pack more tightly together than phosphatidylcholine; the

charged phosphate. The brain synthesizes very-long-chain fatty acids (>20

carbons long); these long uncharged side chains develop strong hydrophobic

associations, allowing close packing of the myelin sheath. The high cholesterol

content of the membrane also contributes to the tight packing, although the

myelin proteins are also required to complete the tightness of the packing

process.

2. Myelin Structural Proteins

The layers of myelin are held together by protein–lipid and protein–protein

interactions, and any disruption can lead to demyelination of the membrane (see

“Biochemical Comments”). Although numerous proteins are found in both the

CNS and PNS, only the major proteins are discussed here. The major proteins in

the CNS and PNS are different. In the CNS, two proteins constitute between

60% and 80% of the total proteins—proteolipid protein and myelin basic

proteins (MBPs). The proteolipid protein is a very hydrophobic protein that

forms large aggregates in aqueous solution and is relatively resistant to

proteolysis. Its molecular weight, based on sequence analysis, is 30,000 Da.

Proteolipid protein is highly conserved in sequence among species. Its role is

thought to be one of promoting the formation and stabilization of the

The MBPs are a family of proteins. Unlike proteolipid protein, MBPs are

easily extracted from the membrane and are soluble in aqueous solution. The

major MBP has no tertiary structure and has a molecular weight of 15,000 Da.

MBP is located on the cytoplasmic face of myelin membranes. Antibodies

directed against MBPs elicit experimental allergic encephalomyelitis (EAE),

which has become a model system for understanding multiple sclerosis, a

demyelinating disease. A model of how proteolipid protein and MBPs aid in

stabilizing myelin is shown in Figure 46.13.

In the PNS, the major myelin protein is P0, a glycoprotein that accounts for

>50% of the PNS myelin protein content. The molecular weight of P0 is 30,000

Da, the same as proteolipid protein. P0 is thought to play a similar structural role

in maintaining myelin structure as proteolipid protein does in the CNS. MBPs

are also found in the PNS, with some similarities and differences to the MBPs

found in the CNS. The major PNS-specific MBP has been designated P2.

V. Glucose Transport through the Blood–Brain Barrier and into Neurons

A hypoglycemic response is elicited by a decrease of blood glucose

concentration to some point between 18 and 54 mg/dL (1 and 3 mM). The

hypoglycemic response is a result of a decreased supply of glucose to the brain

and starts with light-headedness and dizziness and may progress to coma. The

slow rate of transport of glucose through the blood–brain barrier (from the blood

into the cerebrospinal fluid) at low levels of glucose is thought to be responsible

for this neuroglycopenic response. Glucose transport from the cerebrospinal

fluid across the plasma membranes of neurons is rapid and is not rate-limiting

for ATP generation from glycolysis.

In the brain, the endothelial cells of the capillaries have extremely tight

junctions, and glucose must pass from the blood into the extracellular

cerebrospinal fluid by GLUT 1 transporters in the endothelial cell membranes

(Fig. 21.9) and then through the basement membrane. Measurements of the
overall process of glucose transport from the blood into the brain (mediated by

GLUT 3 on neural cells) show a Km,app of 7 to 11 mM and a maximal velocity

not much greater than the rate of glucose use by the brain. Thus, decreases of

blood glucose below the fasting level of 80 to 90 mg/dL (~5 mM) are likely to

significantly affect the rate of glucose metabolism in the brain because of

reduced glucose transport into the brain.