Cells of the nervous system: Neurons & Glial cells ▫ Neurons: –A neuron is Formed of: –Cell body: ▫ contains most of the cytoplasm & organelles –Cytoplasmic extensions: ▫ include an axon & many dendrites Overvie

1. Metabolism of the Brain
(1)
(chemical composition of the
brain)

2. Learning Objectives:
• Explain the chemical composition of the brain,
nervous tissue and myelin
• Discuss the functions of Cholesterol in the CNS
• Identify the characteristic abnormalities in
Alzheimer’s Disease (AD)
• Explain the effects of some natural products on
AD

3. • Central Nervous System (CNS):
▫ Brain and Spinal cord
• Peripheral Nervous System (PNS):
▫ Receptors and Nerves (sensory & motor)
• The CNS is composed of two types of nervous tissues:
i) Gray matter which contains cell bodies,
ii) white matter which contains myelinated axons
Overview of the Nervous System

4. •Cells of the nervous system: Neurons & Glial cells
▫ Neurons:
–A neuron is Formed of:
–Cell body:
▫ contains most of the cytoplasm & organelles
–Cytoplasmic extensions:
▫ include an axon & many dendrites
Overview of the Nervous System (cont,)

5. • Cells of the nervous system: Neurons & Glial cells
▫ Glial cells:
– most abundant cells, are of 3 main types
A. Microglia: Phagocytic (immune) cells,
B. Astrocytes: Support & nutrition of the neurons
(provide neurons with lactate from glucose and
regulate the content of ECF by removing K+ &
excess neurotransmitters)
C. Oligodendrocytes: form myelin sheathe in CNS
– Schwan cells form myelin sheaths in PNS
– Ependymal cells: line brain & spinal cord cavities
using their cilia to allow for the circulation of the
CSF
Overview of the Nervous System (cont,)

6. Chemical composition of the brain
• About 80% of the brain tissue is water
• Most of the brain dry weight is lipids (cholesterol,
phospholipids & glycolipids)
• The remainder of the brain dry weight is proteins
mainly in the neurons and the glial cells

8. Nervous tissue Lipids
•Phospholipids are the most abundant lipids in brain
•Brain Phospholipids are:
▫ Phosphatidylethanolamine (cephalin),
▫ Phosphatidylcholine (lethicin),
▫ Sphingomyelin,
▫ Phosphatidylinositol ,
▫ Phosphatidylserine
▫ Plasmalogen

9. Nervous tissue Lipids
•Cholesterol is the second most abundant substance in
the brain. About 25% of body cholesterol is present in
the nervous tissue.
•Most of cholesterol of adult brain is un-esterified.
Cholesterol easters are found in relatively high
concentrations at sites of active myelinization
•Many of the fatty acids in nervous tissue are
unsaturated and have long carbon chains.
•Brain galactolipids are Cerebrosides, Sulfatides &
Gangliosides

10. Nervous tissue Proteins:
•3 proteins have received some attention:
▫S-100:
–highly acidic protein: 30% of its amino acids are glutamic & aspartic acids
–found in large amounts in glial cells & in small amounts in neurons
–composed of 3 non-identical subunits & has a high affinity for Ca2+
▫Isozyme of enolase (2-phosphoglycerate phosphoenopyruvate)
–highly acidic protein
–found mainly in neurons
▫Both proteins have been implicated with memory or learning
ability of the brain
▫Calmodulin: is needed for the Ca2+-dependent:
–activation of cyclic nucleotide phosphodiesterase enzyme
–release of acetylcholine & nor-epinephrine from their vesicular stores.

11. Nervous tissue Proteins (cont.,):
•The Cytoskeleton of Neurons & Glial cells is made of:
▫ Microtubules:
– composed of both alpha and beta tubulin,
– important for cytoskeletal framework.
▫ Microfilaments:
– composed of actin;
– important for axoplasmic transport
▫ Neruofilaments:
– composed of tau proteins [microtubule-associated protein (MAP)]
– important for cytoskeletal integrity
– tau proteins interact with tubulin to stabilize microtubules, they
degenerate in Alzheimer’s disease through abnormal
phosphorylation

13. • N.B.,
▫ Brain is the only tissue in which the breakdown
products of proteins and phospholipids are
extensively reutilized
▫ The retention and reutilization of brain protein
and lipid seems logical in view of the relative
impermeability of the "blood-brain barrier and
the resistance of the brain to deterioration
during long-term starvation.

14. Chemical composition of Myelin:
• Myelin is a lipid-rich structure formed of lipids and proteins
▫Lipids:
–Cholesterol,
–Phospholipids (phosphatidyl ethanolamine, plasmalogens,
phosphatidylcholine, phosphatidylserine, sphingomyelin &
phosphatidylinositol)
–Galactolipids (cerebrosides, sulphatides & ganglioisides)
–Myelin contains very high levels of cholesterol &
galactocerebrosides
–The major fatty acid associated with these complex lipids
is the mono-unsaturated oleic acid, with
polyunsaturated fatty acids being poorly represented

15. Chemical composition of Myelin (cont.):
▫Proteins:
–2 major myelin proteins in the CNS:
–Proteolipid protein (PLP) is the major myelin protein in CNS
it is an integral protein of oligodendrocyte plasma membrane
–Myelin basic protein (MBP): it is a peripheral protein of
oligodendrocyte plasma membrane; it contains lysine & arginine
–Both PLP & MBP promote the formation & stabilization of the
multilayered myelin structure
–In the PNS,
–Po (a glycoprotein) is the major myelin protein in PNS
–Myelin basic proteins (with some similarities and differences to
the CNS MBPs). The major MBP is designated P2.
–Both proteins have a similar structural role in maintaining myelin
structure, as in the CNS.

17. • N.B.,
▫ Myelin is a tightly packed structure; the layers of
myelin are held together by protein/lipid and
protein/protein interactions, and any disruption can
lead to demyelination of the membrane
▫ Antibodies directed against MBPs elicit
experimental allergic encephalomyelitis (EAE),
which has become a model system for
understanding multiple sclerosis, a demyelinating
disease.

18. Demyelination:
• The importance of myelin in nerve transmission is
highlighted by the wide variety of demyelinating
diseases, all of which lead to neurological symptoms
• Demyelinating Diseases:
▫ Demylination of CNS
– e.g. multiple sclerosis (MS)
▫ Demyelination of PNS
– e.g. Guillain-Barre syndrome (GBS)
▫ Other relatively rare demyelinating diseases

19. • Multiple sclerosis (MS)
▫ MS is believed to result from a bacterial or viral
infection that triggers the formation of
autoimmune antibodies directed against
components of the nervous system leading to
antibody-mediated demyelination
▫ Clinical presentation of MS varies from a mild
disease to a rapidly progressive and fatal disease;
but, the most well-known presentation is the
relapsing-remitting type.

20. •Multiple sclerosis (MS) (cont,)
▫The primary injury to the CNS in MS is the loss of myelin
in the white matter, which interferes with nerve
conduction along the demyelinated area (the insulator is
lost)
▫The CNS compensates by stimulating the oligodendrocyte
to remyelinate the damaged axon, and when this occurs,
remission is achieved.
When it becomes too difficult to remyelinate large areas of
the CNS, the disease progresses
▫Agents that interfere with immune responses succeed in
keeping patients in remission for extended periods.

21. • Guillain-Barre syndrome (GBS)
▫GBS is an acute and progressive neuropathy
believed to result from an autoimmune response
triggered by an illness such as a respiratory or GIT
infection, or by certain vaccines, drugs or even
pregnancy.
• Other relatively rare demyelinating diseases
▫Due to Inherited mutations in Po (the major PNS
myelin protein) or in PLP (the major myelin
protein in the CNS); lead to altered function of
either Po or PLP. This leads to demyelination and
its subsequent clinical manifestations.

22. •Essential role in synaptic plasticity.
•Cholesterol imbalance causes hippocampal neuronal
degeneration.
•Dietary cholesterol increases cholesterol & all
phospholipids synthesis in the hippocampus & cortex
•It is believed that the initial pathophysiologic event
that triggers Alzheimer’s disease (AD) is the change in
the chemistry of soluble amyloid-beta (Aβ) protein
(the most important protein in AD research) due to
chronic modulation of CNS cholesterol.
Functions of Cholesterol in the CNS

23. Alzheimer’s Disease (AD) is Characterized
by Two Abnormalities
1.β Amyloid plaques:
▫ Clumps of insoluble Aβ proteins found in tissue
between nerve cells, along with degenerating
fragments of neurons, and other cells (astrocytes:
explaining astrocytosis seen in AD; glial cells:
explaining the increased incidence of glioma in AD
patients) .
▫ In addition, β amyloid plaques cause oxidative damage
in AD brains by generating free radicals (along with
mitochondrial abnormalities, inflammation, abnormal
antioxidant defense) that play a role in the
pathophysiology of AD.

24. 2.Neurofibrillary tangles:
▫ largely comprising the tau protein (bundles of
twisted filaments found within neurons).
▫ Normally: tau proteins augment the function of
neuronal microtubules. However, if they are
excessively phosphorylated they become
twisted into pairs of helical filaments that collect
in tangles, leading to microtubules
disintegration.
▫ The outcome: collapse of nerve-nerve
communication and finally neuron death.

25. Effects of Some Natural Products on AD
• Nicotinamide/niacinamide (vitamin B3):
▫ Reduce tau protein phosphorylation in AD
patients.
▫ Nicotinamide belongs to a group of compounds
known as: Histone Deacetylase (HDAC) Inhibitors,
that enhance memory.
▫ In rodent models of PD, HD, and ALS, these
compounds have protective effect on CNS.

26. • Curcuminoids in curcumin/turmeric
▫ Stimulate the innate immune system by
increasing the number of macrophages
which clears the β amyloid plaques.
▫ Anti-inflammatory & antioxidant properties
exert the following effects:
– Prevent the development of Aβ plaques in brain.
– Inhibit the formation and extension of Aβ fibrils.
– Destabilization of β amyloid plaques that have
already formed.
– Inhibit neurological proliferation.

27. References:
• Textbook of Biochemistry with clinical correlation 6th ed.
• Harper’s Biochemistry 26th ed.
• Wills’ Biochemical basis of Medicine 3rd ed.
• Koudinova NA, Berezov TT, Koudinova AR. Cholesterol
homeostasis failure: A unifying cause of synaptic degeneration.
Neurobiology of Lipids 3, 7, 2004