Glial Cells and myelination

Question 1

CNS neural cells

Answer 1

neurons (signalling)
glia (astrocytes,OL,microglia)
formed from multipotent neural SC

microglia derived from peripheral myeloid cells

Question 2

roles of glia

Answer 2

development
structural
nutrition (OL/astrocytes for lactate and glucose)
injury
glial scar
phagocytosis (microglia)
myelination (OL)
homeostasis (K+ release/NT removal)

Question 3

what does the brain contain

Answer 3

50% white matter (CC)
50% grey matter

Question 4

why do signals decay along an axon

Answer 4

membrane resistant Rm
axial resistance Ri
membrane capacitance Cm

Question 5

length constant and time constant

Answer 5

length constant = sqrt(Rm/Ri)
time constant = t=RmCm

decrease in Cm - increases time constant/AP

Question 6

myelin G factor/ratio

Answer 6

d1 (axon only)/d2 (axon+myelin)

0.5-0.9
optimal = 0.77

Question 7

myelinated vs unmyelinated axons

Answer 7

unmyelinated - faster if axon <1um, many NaV/KV
myelinated - faster if axon >1um, less energy used, lots of NaV/pumps/nodes/internodes, saltatory conduction, occupies less space than myelinated ones

Question 8

Schwann cells (PNS glia)

Answer 8

1 internode - myelinate a single axon
form non-myelinating Ramak Bundles

Question 9

myelin sheath

Answer 9

evolved independently (dog/prawn/earthworm)
concentric lamellae /fatty insulating layer/saltatory conduction
paranode - node - paranode structure paranode contains cytosol
caspr/contactin/NF155 needed for node formation

Question 10

myelin composition

Answer 10

lipids: cholesterol (27%) synthesis greatest during development , needed throughout life
glycosphingolipids (31%) GalC, used to identify OLs

proteins: 30% fuse and stabilise lamellae, mediate membrane-membrane interactions between myelin lamellae, axons and myelin

Question 11

types of myelin proteins

Answer 11

MBP - fusion of cytoplasmic interface
PLP - fusion of extracellular face of myelin lamellae mutant: myelin unravelling, PMD,leukodystrophy
CNPase (cyclic nucleotide phosphodiesterase) - enzyme specific to OLs, metabolises cAMP, increases adenosine (neuroprotectant) KO - axon degeneration, myelin is unaltered

Question 12

what does a loss of myelin cause

Answer 12

axon dysfunction and degeneration
(MS and other neuropathies)

Question 13

what are OLs derived from

Answer 13

NG2/OPC/polydendrocytes
needed for cognition and motor skills
from birth throughout life

Question 14

what does motor skill learning require

Answer 14

active central myelination (produces new OLs)
OPCs present densely in the hippocampus (learning site)

coexpress NG2 (Cspg4/Pdgfr) susceptible to hypoxia damage

Question 15

signalling which causes myelination

Answer 15

communication via neuro-glial signalling molecules (gliotransmitters): 1)attract OPCs 2) proliferation 3) myelination
axon-OPC (direct) astrocytes (indirect)

Question 16

NTs which affect myelination

Answer 16

adenosine (differentiation and myelination)
ATP
GABA (inhibits differentiation)
glutamate (promotes differentiation)
DA
ACh
BDNF promotes differentiation of myelin by stimulating the proliferation of OPCs

Question 17

Growth factors which affect myelination

Answer 17

PDGF-AA/FGF2 (essential for OPC differentiation)
Wnt/BMP/Notch inhibit OPC differentiation
IGFI stimulates differentiation
Nrg1-Erb regulates myelination

Question 18

decline in generation of OLs

Answer 18

at 60 ~100% have at least one WM lesion
at 70 - 1-10 WM lesions
WM shrinks after 50 yrs
decreased myelin replacement through natural wear and tear

Question 19

developmental myelin pathologies

Answer 19

leukodystrophies (genetic cause)
cerebral palsy

both cause a loss of WM around the ventricles

Question 20

myelin damage causes…

Answer 20

brain injury
infection
toxin
ischaemia/stroke
dementia
bipolar disease
ASD
schizophrenia

Question 21

diseases which cause demyelination

Answer 21

MS
acute disseminated encephalomyelitis
Guilliane Barres Syndrome

Question 22

symptoms of myelin loss

Answer 22

impaired vision (optic nerve is where demyelination is first seen)
impaired hearing
memory loss
loss of dexterity

Question 23

who gets MS

Answer 23

1 in 1000 in the UK
females are more likely
age range: 15-50
mean onset: 28m 33f
prognosis: LT
5-10yrs reduced lifespan

Question 24

what is MS

Answer 24

autoimmune disease
where the immune cells attack myelin
demyelination occurs in flares (relapses) then remyelination occurs (complete but thin and risk of failing)

Question 25

genetic and environmental factors which cause MS

Answer 25

HLA class II gene (susceptibility gene)
associated gene: APOE/CNTF/osteopontin

environmental: EBV (after 15yrs) systemic infections

Question 26

MS pathogenesis

Answer 26

relapsing/remitting (90%) - periods of demyelination followed by partial remyelination
primary progressive (10%) - demyelination becomes more widespread and patient deteriorates slowly with no remission - astrocyte scarring and failure of remyelination

Question 27

physical MS pathogenesis

Answer 27

CNS lesions in the SC causes numbness and weakness
optic nerve degeneration causes visual disturbances
cerebellum - ataxia/BS vertigo
no cure but therapies ameliorate symptoms

Question 28

MS phases

Answer 28

preclinical
demyelination
remyelination
inactive/chronic demyelinating plaque

Question 29

preclinical stage of MS

Answer 29

early phase lesion formed w/o clinical signs
depends on immune cells crossing BBB
triggers microglial activation without demyelination

Question 30

microglia

Answer 30

distributed in mosaic pattern throughout CNS
5% all brain cells
phagocytic/immune cells
express many receptors (ON/OFF) - cellular damage releases ATP (microglia contain ATP R)

Question 31

microglia activation states

Answer 31

M1 classically activated (proinflammatory, release TNFa/NO) associated with acute infection- damage OL/myelin
M2 alternatively activated (anti-inflammatory - associated with tissue remodelling) releases FGF2 which promotes remodelling
but…multiple intermediate phases

Question 32

4 patterns of MS lesions (demyelination)

Answer 32

I - inflammatory cell infiltrate (macrophages B/T cells)
II - like pattern I lesions (added with complement and antibodies)
III - oligodendrocyte apoptosis little infiltration, macrophages are present
IV - 1% of lesions, OL death (non-apoptotic)

Question 33

remyelination

Answer 33

thinner myelin and sheaths
requires adult OPCs (co-express NG2 - Cspg4) and Pdgfra

Question 34

inactive/chronic demyelinating plaque

Answer 34

inside plaque there is a loss of myelin and OLs
plaques are acellular with few glia (small/fibrous astrocytes)
dense astrocytic gliosis

Question 35

why does remyelination fail

Answer 35

decline in OL regeneration
loss of replacement of myelin
MS neurodegeneration - due to a lack of GF? Pdgf-aa FGF2 or inhibitory factors? Notch/wnt/bmp/astrocytic scars

Question 36

Licensed MS drugs

Answer 36

B-interferon - reduces and prevents inflammation (e.g. Avonex)
Copaxone/glatiramer acetate - myelin decoy for the immune system (polymer of 4aa in MBP), reduces immune cell entry (e.g. Tysabri)

Question 37

drugs in current trials to treat MS

Answer 37

monoclonal antibodies (Daclizumab - targets CD25 on immune cells)/Rituximab (targets CD20 on Bcells)
anti-inflammatory drugs (Minocycline/simvastin for secondary progressive MS)
Anti-viral (Raltegravir)
Metformin - stimulates myelination by mimicking fasting (reduces blood sugar)

Question 38

future therapies

Answer 38

phase II - anti-LINGO used in myelin repair
stem cell therapy - obtain haematopoietic SC - chemotherapy (remove immune cells) inject SC - isolation (only used in severe MS)

Question 39

TRPA1

Answer 39

non-specific cation channel (Ca2+ permeable)
activated during ischaemia (stroke/low O2/glucose)
damages myelin
constitutively active and regulates the excitability of axons
agonists - decrease amplitude of compound action potential

Question 40

TRPA1 antagonists

Answer 40

FFA
increase Ca2+ increases amplitude of compound AP (measure CAPs in adult optic nerve - Lajoso et al)
prevents WM loss