Block I presentation Martins Flashcards
1
Q
what do schwann cells do?
A
Promote axonal regeneration and are derived from neural crest
2
Q
What cells produce myelin in the CNS?
A
Oligodendrocytes
3
Q
What cells produce myelin in the PNS?
A
Schwann cells
4
Q
HOw much does a shwann cell myelinate?
A
1 shwone myelinates 1 PNS axon
5
Q
How much does an oligodendrocyte myelinate?
A
Each oligo can myelinate many axons (~30)
6
Q
What is the predominantly type of glial cell in white matter?
A
oligodendrocytes, derived from neuroectoderm
7
Q
what structures are present in the sodium channels?
A
Nodes of ranvier
8
Q
What are the main functions of the nodes of ranvier?
A
propagate action potentials via saltatory
conduction
9
Q
What sodium channels are present in CNS and PNS
A
Nav1.2
10
Q
what happens when there is maturation?
A
Nav1.3 is downregulated; while Nav1.6 compensates
11
Q
What happens with sodium channels on early myelination?
A
co- localization of Nav1.2 and Nav1.6
clusters
12
Q
What happens if spaces of node of ranvier are too big?
A
It dissipates
13
Q
What is the node of ranvier?
A
Foot (non myelinated axon)
14
Q
Microglia emerges from?
A
messenchymal
15
Q
What protein is specific of PNS (hint electrophoresis)
A
Po; present in human and rat PNS electrophoresis
16
Q
When does myelinization begin?
A
During the fetal period and continues during the first postnatal year
17
Q
When does myelinization tends for be complete?
A
around the same time be complete the fibers
become functional
18
Q
Which fibers myelinate first?
A
motor fibers > SENSORY FIBERS
19
Q
What is the main purpose of myelin?
A
increase the conduction of speed of
electrical signals between neurons while reducing energy requirements
20
Q
Where do oligodendrocytes emerge from?
A
stem cells/ectoderm
21
Q
What myelin protein is present in both CNS and PNS?
A
MBP, pero hay mas en la CNS
22
Q
What protein is from CNS exclusively?
A
MOG
23
Q
What structure is myelinized last?
A
Forebrain
24
Q
What structure is myelinized first?
A
spinal cord
25
When does myelinization of forebrain starts?
13-14 years; decision making social skills
26
myelinization final stops by?
~30 years
27
How much does myelin increase conduction?
6 times more
28
Multiple sclerosis?
CNS
29
Guillian barre?
PNS
30
What are the steps of myelinization of axonal nerves?
- Glia polarization
- Expansion and compaction of myelin.
* Separation of axoplasm from extracellular milieu (nutrient deprivation bc it closes)
* Glia support axonal energy Metabolism.
* Gap junction linkage of local stacks of non-compacted myelin.
31
What are Schimdt Lanterman incisures? (SLI)
a circular-truncated cone shape in the
myelin internode that is a specific feature of myelinated nerve fibers formed in Schwann cells in the peripheral nervous system (PNS).
32
What are the functions of the SLI?
serving 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.
33
Where are sodium channel located?
Nodes of ranvier
34
Explain the Na channels
When Na channels are inrefractory period they are closed and inactivated, when an axon potential comes they open and depolarize, closing thus, opening K channels influx
35
What is Multiple sclerosis?
Chronic disease that damages the nerves
in the white matter of the CNS and spinal
cord.
Does not involve peripheral nerves
(5%).
Immune system attacks myelin Optic
nerve lesions are common.
Scarring of tissue in response to the
nerve damage.
Symptoms: problems with muscle
control, balance, vision, or speech.
36
What is Experimental allergic encephalomyelitis (EAE)?
Used as experimental model for
investigation of demyelination.
* Immunopathology and neuropathology
mechanisms leads to key pathological
features of MS: inflammation,
demyelination, axonal loss and gliosis in
the CNS.
* May occur following viral infections or
vaccinations (i.e. post infectious
encephalomyelitis).
generates cytokines and kills macrophages; model to destroy myelin
37
WHat is Guillian barre symptom?
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 blood K+ levels).
38
How many markers does oligodendrocytes have?
5-100, O4
39
What is S100?
Specific marker for schwann cell
40
What is the composition of BBB?
1. endothelial cells lining the capillary wall with tight junctions between them.
(2) processes of astrocytes abutting on the capillaries as perivascular end-feet.
(3) a capillary basement membrane.
(4) pericytes
41
what is the function of the BBB?
The blood-brain barrier (BBB) is the specialized system of brain microvascular endothelial cells
(BMVEC) that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream.
42
Why are endothelial cells different from peripheral cells?
because of tight junctions, transport system,
43
WHta quantity does not pass through the pericyte?
more than 500 dalton
44
What proteins are present in the basement membrane of bbb?
Collagen IV, Lamins, agrin
45
What is present on an endothelial cell?
Tight junctions and increased density of mitochondria
46
Which protien is the most important?
Claudin IV
47
Describe the basement memebrane of bbb
The BM is a sheet-like ECM (extracellular matrix) complex beneath epithelium
and endothelium.
At the BBB, the BM encircles the abluminal side of blood vessels and is located
at the interface of the circulation system and central nervous system
48
of what major proteins does the Basement membrane consist?
collagen IV, laminin, nidogen, perlecan,
and agrin
49
Which proteins have heparan sulfate proteoglycan?
Perlecan and agrin
50
What differentiates endotehlial cells of intracerebral vessels?
reduced density of caveolae and the presence of circumferential tight junctions between endothelial cells and increased density of mitochondria
51
What substances can pass through endothelium?
wide range of lipid-soluble molecules can diffuse through the endothelium and enter brain passively
52
Which molecules pass the endothelium more easy?
Bases, 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 an interaction with the negatively charged glycocalyx and phospholipid head groups of the outer leaflet of the cell membrane that facilitates their entry
53
What type of transport does the Transcellular bidirectional transport across cerebral endothelium occur?
receptor-mediated transport, carrier-mediated transport, ion transport, peptide transport, and active efflux transport.
54
What does carrier-mediated transport facilitates?
transport of nutrients into brain including hexoses (glucose, galactose)
neutral, basic and acidic amino acids, and monocarboxylic acids (lactate, pyruvate, ketone bodies)
nucleosides (adenosine, guanosine, uridine)
purines (adenine, guanine), nucleotides,
nucleobases, organic anion, and organic cations; amine and vitamins
55
How much claudins are there?
4 transmembranal proteins
56
Where are claudins present?
Zona occludens
57
Where are tight junctions present?
Tight junctions are present at the apical end of the interendothelial space being intimately connected to and dependent on the cadherin
based adherens junctions which are located near the basolateral side of the interendothelial space
58
What do tight junctions prevent passing?
tracers such as HRP horseradish peroxidase
59
What hydrophilic molecules can pass in tight junctions?
sodium, hydrogen, bicarbonate, and other ions
60
gate or barrier?
Tight junctions
61
What is the fence function?
Tight junctions also restrict the movement of membrane molecules between the
functionally distinct apical and basolateral membrane surfaces
62
HOw many paralle strands are in tight junctions?
8-12 with no discontinuities
63
Describe claudins`
Claudins are 18–27-kDa tetraspan proteins with a short cytoplasmic Nterminus, two extracellular loops, and a COOH terminal cytoplasmic domain which ends in valine
64
Which are considered the main structural components of intramembrane strands and recruit occludin to tight junctions?
Claudins
65
Which claudin regulates size-selective diffusion of small molecules?
Claudin 5, increased paracellular permeability to molecules <800D
66
Where are tight junctions located?
cholesterol-enriched regions along the plasma
membrane associated with Cav-1.
67
Of what have studies demonstrated that tight junctions are 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 while remaining capable of rapid modulation and regulation
68
What are the two tetraspan trasnmembrane proteins?
Claudin family and occludin
69
Which is the single-span transmembrane protein?
junction adhesion molecule (JAM) family of proteins.
70
What do the tetraspan proteins form?
form the paracellular permeability barrier and
determine the capacity and the selectivity of the paracellular diffusion pathway
71
Describe occludin
a 60 kDa protein, participates in forming and maintaining the barrier between adjacent cells and acts as a fence to restrict movement of lipids and proteins between the apical and lateral domains
72
Where occludin present?
present in most occluding junctions
73
Do all edothelial cells have occludin?
No, but possess well-developed and fully functional zonulae occludentes
74
is occludin required for assembly of intramembrane strands ate tight junctions?
no, its a regulatory protein
75
What are JAMs?
Junctional adhesion molecule (JAM) is a 40 kDa protein that belongs to the immunoglobulin superfamily (IgSF).
76
What is the fucntion of JAM?
It is responsible for increasing the electrical resistance of the cell membrane, thereby reducing paracellular permeability
involved in the formation of occluding junctions in endothelial cells as well as between endothelial cells and monocytes migrating from the vascular space to the connective tissue
77
With what protein is JAM asociated?
not itself form a zonula occludens strand but is instead associated with claudins.
78
WHat happens if there is overexpression of JAM?
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
79
What are PDZ-domain proteins?
zonula occludens proteins ZO-1, ZO-2, and ZO-3
80
Functions of PDZ
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.
81
What does Evans blue do?
Attaches to albumin so that albumin does not pass to the brain
82
What are some finctions of microglia?
1. Immune role in CNS
2. Maintain central homeostasis
3. Combat disease: neuroprotective role
(microglia>phagocytic macrophages)
4. Development (promote axonal growth and migration)
5. Comprise 10-20% of total glia cells in adult
6. Contain neurotransmitter receptors
7.Important feature: polarization [M0-resting; M1- inflammatory; M2-anti-inflammatory
83
What is the M1 marker?
iNOS
84
What is the M2 marker?
Arginase I
85
What is caveolae?
can open both the luminal and albuminal plasm.
Intracerebral cortical vessels contain a mean of 5 caveolae/mm2 in arteriolar and
capillary endothelium a membrane through a neck 10–40 nm in diameter
Cerebral endothelium contains 14-fold fewer vesicles as compared with endothelium of
nonneural vessels such as myocardial capillaries. The decreased number of vesicles
in cerebral endothelium implies limited transcellular traffic of solutes in steady states
86
What happens in capillaries in areas where bb is absent?
such as the subfornicial organ and area postrema, are highly permeable and have significantly higher numbers of endothelial caveolae
87
Functions of caveolae
vesicular trafficking in transcytosis of proteins, endocytosis, and potocytosis
regulate a wide variety of signaling molecules.
function in the regulation of cell cholesterol and glycosylphosphatidylinositol (GPI)-linked proteins, in cell migration, as docking sites for
glycolipids and as flow sensors
Endothelial caveolae are involved in endocytosis, a process by which the permeant
molecules are internalized within endothelial cells or they may be involved in transfer of
molecules from blood across the cell to the interstitial fluid or in the reverse direction, a
process termed transcytosis
88
What transport depends on ATP? And what is its inhibitor?
Both endocytosis and transcytosis may be receptor-mediated or fluid phase and require
ATP and can be inhibited by N-ethylmaleimide (NEM), an inhibitor of membrane fusion
89
What is the molecular structure of caveolae?
generally accepted as a lipid raft.
membrane is enriched in b-d-galactosyl and b-N-acetylglucosaminyl residues in palmitoleic and stearic acids and in cholesterol and sphingolipids (sphingomyelin and glycosphingolipid).
90
What is the function of sphingolipids?
substrates for synthesis of a second intracellular messenger, the ceramides
91
What molecules provides support for caveolae?
Cholesterol provides a structural support for caveolae and creates the frame in which many caveolar molecules are inserted.
92
Which caveolae are expressed in endothelial cells of the brain?
Cav-1 and 2
93
Which caveolae are expressed in astrocytes?
Cav-3
94
What are the isoforms of cav-1?
a and b and brain cells express predominantly the a -isoform
95
WHta is cav-1?
the specific marker and major component of caveolae, is an integral membrane
protein (21–24 kDa) having both amino and carboxyl ends exposed on the cytoplasmic
aspect of the membrane (30).
96
What is transcytosis?
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
97
What transcytosis processes does caveolae take part?
vesicleassociated membrane protein-2 (VAMP-2),
monomeric and trimeric GTPases, annexins II and IV, N-ethyl maleimide (NEF)-sensitive fusion factor (NSF), and its attachment protein – soluble NSF attachment protein (SNAP) and vesicle-associated SNAP receptor (v-SNARE).
98
Technique used to measure paracellular transport?
Sucrose in brain serum
99
Which receptors are invovled in receptor mediated transcytosis?
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
100
what other factors are present in receptor mediator trasncytosis?
death receptors which are involved in cell apoptosis and include receptors for p75 and interleukin-1.
101
What is the technique to measure transcytosis?
albumin in brain serum
102
What is an Efflux transport?
Active efflux transport involves a transporter, which utilizes ATP to shuttle drugs and other solutes out of the brain and into the blood compartment
103
What do efflux do with drugs?
minimize effective drug penetration into
brain parenchyma, thus limiting the efficacy of
drugs targeted at brain diseases
104
What is the substrate in efflux transport?
verapamil
105
P-gp transport potential was evaluated by
quantifying 3Hverapamil accumulation in the brain in proportion to that in the perfusate.
106
What organs lack BBB?
Circumventricular organs, in the midline of the ventricular system; pineal, subcommissural organ, area postrema, pituitary gland, median eminence, organum vasculosum, subfornical organ
107
Why do circumventricular organs lack bbb?
Discontinuous tight junctions between endothelial cells allow entry of molecules
108
mention some strategies for delivering therapeutic treatments across the bbb?
Paracellular difussion: ultrasound and hyperosmotic agents
Trancellular pathway:
-drug modification:
1. lipidization
2. targeting moieties attachment
-carrier-based delivery:
1.nanoparticles
2.cells
109
What do astrocyte end feet do?
provide structural integrity to the cerebral vasculature
110
Explain brain metabolism
2% of body weight
20% energy demand
25% glucose
111
What does the body use during brain development and in the adult during prolonged fasting periods
ketone bodies
112
WHat hapens during prolonged fasting> (5-6 weeks)
ketone body levels rise significantly and are able to contribute almost 60% of the brain’s
energy requirement, thereby replacing glucose as the main fuel
113
What does the body use during increased physical activity?
Lactate
114
How is glut-1 present in the brain?
as 2 distinct molecular forms with molecular weights of 55- and 45-kDa, which are encoded by the same gene and differ only in their extent of glycosylation.
115
where is the 55-kDa isofrom of glut1 detected?
detected exclusively in brain endothelial cells
116
where is the 25-kDa isofrom of glut1 detected?
expressed in neurons and glial cells
117
What is Glut1DS?
Glucose transporter type 1 deficiency syndrome (Glut1DS) is a rare genetic metabolic
disorder characterized by deficiency of a protein that is required for glucose to cross the blood-brain barrier and other tissue barriers. need keto diet to survive
118
What do neurovascular and neurometabolic couple do?
enhance blood flow and utilization of metabolites in areas of neural activity
119
What increases in localized regions of activity following neuronal stimulation?
Cerebral blood flow (CBF), blood volume, glucose consumption and oxygen
metabolism
120
What is the gatekeepoer of neurological function?
claudin-5
121
BBB impairment
Meningitis, alzheimer, MS, peilepsy, Stroke, parkinson, brain tumor, Schizophrenia, HIV encephalitis
122
Hypoxic
insufficient oxygenation
123
Ischemic
insufficient blood-flow
124
Anemic
insufficient hemoglobin
125
Lack of energy =
electrical failure
126
Last long enough =
arrest of cellular functions and cell death
127
Steps of hypoxia
First result of energy depletion:
failure of sodium and potassium pumps
Depolarization
Glutamate release
Overactivation of non-selective
cation-permeable ion channels >
Cl- passive influx into cells (osmotic
edema and rapid death)
128
Hypoxia/ischemia of endothelial cells result in?
Angiogenesis and vascular remodeling
Increased vascular permeability
129
Hypoxia/ischemia of basement emembrane cells result in?
Angiogenesis and vascular remodeling
Edema and hemorrage formation
130
Hypoxia/ischemia of astrocytes cells result in?
Edema and hemorrage formation
Increased vascular permeability
131
Hypoxia/ischemia of tight junctions result in?
Increased vascular permeability
132
Hypoxia/ischemia of pericytes result in?
Increased vascular permeability
decreased vascular stability
