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Neuro > Myelin and BBB Metabolism > Flashcards

Myelin and BBB Metabolism Flashcards

1
Q

In CNS Myelin is synthesised by

A

Oligodendrocytes

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2
Q

In PNS Myelin is synthesized by

A

Schwann Cells

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3
Q

Oligodendrocytes

A

Can myeline many axons at a time (30)
Derived from neuroectoderm
Injured in Multiple sclerosis, progressive multifocal leukoencephalopathy, leukodystrophies

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4
Q

Schwann Cells

A

Myelinates one axon at a time
Derived from the neural crest
Involved in axonal regeneration
Injured in Guillain Barre Syndrome

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5
Q

Marker for Schwann cells

A

S-100

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6
Q

Blood Brain Barrier

A

Prevents circulating blood substances (bacteria, drugs etc) reaching the CSF/CNS.

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7
Q

BBB Formed by four structures:

A

Tight junctions between nonfenestrated capillary endothelial cells
Basement membrane
Pericytes
Astrocyte foot processes

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8
Q

Glucose and amino acids cross the BBB…

A

Slowly by carrier-mediated transport mechanisms

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9
Q

Circumventricular organs are

A

are structures that permit polypeptide hypothalamic hormones to leave the brain without disrupting the blood-brain barrier (BBB) and permit substances that do not cross the BBB to trigger changes in brain function.

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10
Q

Examples of circumventricular organs:

A

Area postrema (vomiting after chemotherapy)
Organum Vasculosum Lamina Terminales (OVLT) (osmoreceptors)
Neurohypofisis (ADH Release)

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11
Q

Example of BBB disruption…

A

Stroke (vasogenic edema)

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12
Q

Hyperosmolar agents like mannitol can disrupt the BBB and increase…

A

the permeability of medications to enter the BBB

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13
Q

The sodium channels are highly enriched in

A

Nodes of Ranvier to propagate action potentials via saltatory conduction

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14
Q

Myelination begins during…

A

The late fetal period and continues during the first postnatal year

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15
Q

Myelination tends to be complete around…

A

The same time the fibers become functional

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16
Q

Motor fibers tend to be

A

Myelinated before sensory fibers

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17
Q

Myelin is

A

White lipid-rich insulating membrane that wraps around some axonal projections.
Increases conduction of speed of electrical signals between neurons while reducing energy requirements

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18
Q

Myelination of Axonal Nerves is a multistep process:

A

Glia polarization
Expansion and compaction of myelin
Separation of axoplasm from extracellular milieu (nutrient deprivation)
Glia support axonal energy metabolism
Gap junction linkage of local stacks of non compacted myelin

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19
Q

Schmidt Lantern incisure

A

is a circular truncated cone shape in the myelin internode that is a specific feature of myelinated nerve fibers ford in Schwann cel in the PNS

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20
Q

Schmidt Lantern incisure functions

A

Serves as a cytoplasmic channel connecting the inner and outermost aspects of the myelin sheath, formation and structural stability of myelin, regulation of adhesion, and signal transduction.

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21
Q

Sodium channel clustering at nodes of Ranvier

A

Prior to myelination, sodium channels are present throughout the axonal membrane at low density
Upon Schwann cell adherence and axonal myelination > sodium channel clustering

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22
Q

Myelin pathologies

A

Multiple sclerosis
Guillain Barre Syndrome

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23
Q

Multiple Sclerosis

A

Chronic disease that damages the nerves in the white matter of the CNS and spinal cord
Does not involve peripheral nerves
Scarring of tissue in response to the nerve damage
Symptoms: problems with muscle control, balance, vision or speech

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24
Q

Experimental autoimmune encephalomyelitis

A

Used as an experimental model for investigation of demyelination.
Immunopathology and neuropathology mechanisms lead to key pathological features of MS : inflammation, demyelination, axonal loss and gliosis in the CNS.
May occur following viral infections or vaccinations

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25
Q

Guillain Barre Syndrome

A

Autoimmune disease: attack peripheral nerve myelin (Schwann cell myelination)
Onset of disorder: Fear and anxiety)
Symptoms: pain, muscle weakness and paralysis, weakness of breath muscles
Diagnosis: rapid development of muscle paralysis, absence of reflex, CSF fluid analysis, nerve conduction studies, blood tests (not due to low K+ levels)

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26
Q

Blood Brain Barrier

A

Is the specialized system of brain microvascular endothelial cells that shields the brain from toxic substances in the blood, supplies the brain tissues with nutrients, and filters harmful compounds from brain back to the bloodstream

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27
Q

Basement membrane

A

Is a sheet-like extracellular matrix complex beneath epithelium and endothelium.
At the BBB, the basement membrane encircles the abluminal side of blood vessels and is located at the interface of the circulation system and central nervous system

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28
Q

Train Basement Membrane concise of 5 major proteins:

A

Collagen IV, laminin, nidogen, perlecan and agrin

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29
Q

Endothelial cells have many properties that are similar to those present in nonendothelium including

A

the expression of glycoproteins, adhesion molecules, and integrin receptors

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30
Q

Morphological features of endothelial cells

A

Reduced density of caveolae and the presence of circumferential tight junctions between endothelial cells
Also have increased density of mitochondria

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31
Q

Endothelial transport
Lipid molecules

A

Can diffuse through the endothelium and enter the brain passively

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32
Q

Endothelial transport
Bases

A

Which carry a positive charge have an advantage over acids in penetration of endothelial cells and it is probably the cationic nature of these molecules and interaction with the negatively charged glycocalyx and phospholipid head groups of the outer leaflet of the cell membrane that facilitates their entry

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33
Q

Endothelial transport
Transcellular bidirectional transport

A

Occurs by receptor-mediated transport, carrier-mediated transport, ion transport, peptide transport, and active efflux transport

34
Q

Endothelial transport
Transcellular bidirectional transport
Carrier-mediated transport systems facilitate…

A

Transport of nutrients into the brain including hexoses (glucose, galactose); neutral, basic, and acidic amino acids, mono-carboxylic acids (lactate, pyruvate, ketone bodies): nucleosides (adenosine, guanosine, uridine); purine (adenine, guanine), nucleotides, organic anion and organic cations: amine and vitamins

35
Q

Tight junctions between endothelial cells composed of:

A

Claudins
Occludin
JAMs

36
Q

Endothelial junctions

A

Tight junctions are present at the apical end of the interendothelial space, intimately connected to and dependent on the cadherin-based adherents junctions located near the baser-lateral side of the interendothelial space.
Forms a pentalaminar structure which prevents the passage of tracers

37
Q

These tight junctions extend circumferentially around the endothelial cells forming a barrier to

A

paracellular passage of small hydrophilic molecules such as sodium, hrydogen, bicarbonate and other ions

38
Q

Tight junctions also restrict the movement of membrane molecules between functionally distinct

A

apical and basolateral membrane surfaces

39
Q

Claudin family

A

Consists of 24 members in mice and humans and exhibit distinct expression patterns in tissue and cells
Are 18-27 kD tetraspan protein
They are considered to be the main structural components of intramembrane strands and recruit occludin to tight junctions

40
Q

Claudin-5

A

regulates size selective diffusion of small molecules since Claudin 5 knockout mice show increased paracellular permeability to molecules <800D

41
Q

Tight Junctions
Localization and structure

A

Are localized at cholesterol-enriched regions along the plasma membrane associated with Cav-1
Composed of an intricate combination of tetraspan and single-span transmembrane and cytoplasmic proteins linked to an actin-based cytoskeleton that allows these junctions to seal the paracellular space with remaining capable of rapid modulation and regulation.

42
Q

Tetraspan proteins

A

Form the paracellular permeability barrier and determine the capacity and the selectivity of the paracellular diffusion pathway

43
Q

Tight Junctions
Tetraspan transmembrane proteins are

A

Claudin Family
Occludin

44
Q

Tight Junctions
Single-span transmembrane protein is

A

JAM family of proteins (junction adhesion molecule)

45
Q

Occludin

A

60 kDa protein
Participates in forming and maintaining the barrier between adjacent cells and acts as a fence to restrict the movement of lipids and proteins between the apical and lateral domains. Occludin is present in most occluding junctions.

Several types of epithelial cells do not have occludin within their strands at tight junctions but still possess well-developed and fully functional zonulae occludentes.
Occludin is a regulatory protein, associated with the intramembrane strands at tight junctions, although is not required for their assembly.

Occludin knockout mice are still capable of forming interendothelial tight junctions having normal morphology and barrier function in intestinal epithelial cells, while Claudia knockout mice are nonviable.

46
Q

JAM

A

Is a 40 kDa protein that belongs to the immunoglobulin superfamily. (IgSF)
Does not itself form a zonula occludens strand but is associated with Claudius. It is responsible for increasing the electrical resistance of the cell membrane, thereby reducing paracellular permeability.

Overexpression of JAMs in cells that do not normally form tight junctions increases their resistance to the diffusion of soluble tracers, suggesting that JAM functionally contributes to permeability control

47
Q

PDZ-domain proteins

A

Zonula occludens proteins ZO-1, ZO-2 and ZO-3
Regulatory functions during the formation of the zonula occludens have been suggested for all ZO proteins. In addition, ZO-1 is a tumor suppressor, and ZO-2 is required in the epidermal growth factor receptor signaling mechanism. The ZO-3 protein interacts with ZO-1 and the cytoplasmic domain of occludins.

48
Q

Microglia

A

Immune role in CNS
Maintain central homeostasis
Combat disease: neuroprotective role (microglia > phagocytic macrophages)
Development (promote axonal growth and migration)
Comprise 10-20% of total glia cells in adults
Contain neurotransmitter receptors
Important feature: polarization
M0 resting
M1 Inflammatory
M2 Anti-inflammatory

49
Q

M1 Marker

A

iNOS

50
Q

M2 Marker

A

Arginase 1

51
Q

Caveolae

A

Are flask-shaped membrane-bound vesicles having a mean diameter of 70nm which can be open to both the luminal and abluminal plasm

The decreased number of vesicles in cerebral endothelium implies limited transcellular traffic of solutes in steady states.

In contrast, capillaries in areas where a BBB is absent such as the subfornical organ and area postrema, are highly permeable and have significantly higher numbers of endothelial caveolae.

52
Q

Function of caveolae

A

Involved in the process of vesicular trafficking in transcytosis of proteins, endocytosis and pinocytosis

Endocytocis and transcytosis may be receptor-mediated or fluid phase and require ATP and an be inhibited by N-ethylmaleimide (NEM), an inhibitor of membrane fusion.

Regulation of cell cholesterol and GPI-linked proteins, in cell migration, as docking sites for glycolipids and as flow sensors.

53
Q

Endothelial caveolae functions

A

Involved in endocytosis, a process by which the permeant molecules are internalized within the endothelial cells or they may be involved in the transfer of molecules from blood across the cell to the interstitial fluid or in the reverse direction, a process termed as transcytosis

54
Q

Transcytosis

A

transfer of molecules from the interstitial fluid across the cell to the blood

55
Q

Molecular Structure of Caveolae

A

Is a lipid raft
Membrane is enriched in b-d-galactosyl and b-N-acetylglucosaminyl residues in palmitoleic and stearic acid and in cholesterol and sphingolipids

Located in the coat of caveolae are the caveolin (Can) family of proteins, which comprise three members named Cav-1, Cav-2, Cav-3

56
Q

In the brain Cav-1, Cav-2 are primarily expressed in…

A

Endothelial cells

57
Q

Cav-1

A

The specific marker and major component of caveolae.
Is an integral membrane protein.
21-24kDa
In the brain the cells predominantly express the alpha isoform

58
Q

In the brain Cav-3 is primarily expressed in…

A

Astrocytes

59
Q

Sphingolipids

A

Are substrates for synthesis of a second intracellular messenger

60
Q

Cholesterol

A

Provides a structural support for caveolae and creates the frame in which many caveolar molecules are inserted

61
Q

Transcytosis

A

Is a multistep process that involves successive caveolae budding and fission from the plasma membrane, translocation across the cell, followed by docking and fusion with the opposite plasma membrane.

Caveolae contain the molecular machinery for these processes: VAMP2, monomeric and trimeric GTPases, annexins II and IV, NEF, NSF, SNAP, V-SNARE

62
Q

Receptor mediator transcytosis

A

Receptors present in caveolae membranes are involved in receptor-mediated transcytosis of low- and high-density lipoprotein, epidermal growth factor, tumor necrosis factor, albumin, transferrin, melanotransferrin, lactoferrin, ceruloplasmin, transcobalamin, advance glycation end products, leptin, and insulin, all of which are essential in maintaining cell and tissue homeostasis and are therefore referred to as the life receptors.

Also present are death receptors which are involved in cell apoptosis and include receptors for p75 and interleukin-1.

63
Q

P-gp Efflux Transport)

A

Active efflux transport involves a transporter, which utilizes ATP to shuttle drugs and other solutes out of the brain and into the blood compartment.

Minimize effective drug penetration into the brain parenchyma, thus limiting the efficacy of drugs targeted at brain diseases

Verapamil is a substrate

64
Q

Strategies to facilitate the delivery of therapeutic agents across the barriers

A

Disruption of BBB
Drug modification
Carrier based delivery

65
Q

Disruption of BBB

A

Paracellular diffusion
-Ultrasound
Hyperosmotic agents

66
Q

Drug modification

A

Transcellular diffusion
-Lipidization- transcytosis of lipid molecules
-Targeting moieties attachment
Transporter mediated pathway
Adsorptive transcytosis

67
Q

Carrier based delivery

A

Transcellular pathway
-Nanoparticles
- Cells
Receptor mediated pathway
Inhibition of efflux transporter

68
Q

Astrocyte end-feet

A

Ensheate blood vessels in the brain and are believed to provide structural integrity to the cerebral vasculature

69
Q

Brain metabolism

A

2% of body weight
20% energy demand
25% of glucose

70
Q

Ketone bodies

A

Are utilized during brain development and in the adult during prolonged fasting periods.

During prolonged fasting (5-6 weeks), ketone body levels rise significantly and are able to contribute almost 60% of the brains energy requirements, thereby replacing glucose as the main fuel

71
Q

Lactate

A

Utilization is increased during intense physical activity.

72
Q

GLUT1

A

In the brain GLUT-1 is present as 2 distinct molecular forms with molecular weights of 55 and 45kDa, which are encoded by the same gene and differentiation only in their extent of glycosylation.

73
Q

55kDa isoform of GLUT1

A

Detected exclusively in brain endothelial cells

74
Q

45 kDa isoform of GLUT1

A

Expressed in neurons and glial cells

75
Q

Glucose transporter type 1 deficiency syndrome (Glut1DS)

A

Characterized by deficiency of a protein that is required for glucose to cross the blood-brain barrier and other tissue barriers.

76
Q

Neurovascular coupling

A

Cerebral blood flow, blood volume, glucose consumption and oxygen metabolism are all increased within localized regions of activity following neuronal stimulation

77
Q

Neurovascular and Neurometabolic Coupling

A

To compensate for varying energy demands throughout the brain and to increase efficiency of metabolite supply, neuromuscular and neurmetabolic coupling mechanisms have evolved to enhance blood flow and utilization of metabolites in areas of neural activity

78
Q

Hypoxia (three types)

A

Hypoxic
Ischemic
Anemic

79
Q

Hypoxia Hypoxic

A

insufficient oxygenation

80
Q

Hypoxia ischemic

A

insufficient blood-flow

81
Q

Hypoxia Anemic

A

insufficient hemoglobin

82
Q
A

Neuro (4 decks)

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