Glial Cells and myelination Flashcards
CNS neural cells
neurons (signalling)
glia (astrocytes,OL,microglia)
formed from multipotent neural SC
microglia derived from peripheral myeloid cells
roles of glia
development
structural
nutrition (OL/astrocytes for lactate and glucose)
injury
glial scar
phagocytosis (microglia)
myelination (OL)
homeostasis (K+ release/NT removal)
what does the brain contain
50% white matter (CC)
50% grey matter
why do signals decay along an axon
membrane resistant Rm
axial resistance Ri
membrane capacitance Cm
length constant and time constant
length constant = sqrt(Rm/Ri)
time constant = t=RmCm
decrease in Cm - increases time constant/AP
myelin G factor/ratio
d1 (axon only)/d2 (axon+myelin)
0.5-0.9
optimal = 0.77
myelinated vs unmyelinated axons
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
Schwann cells (PNS glia)
1 internode - myelinate a single axon
form non-myelinating Ramak Bundles
myelin sheath
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
myelin composition
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
types of myelin proteins
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
what does a loss of myelin cause
axon dysfunction and degeneration
(MS and other neuropathies)
what are OLs derived from
NG2/OPC/polydendrocytes
needed for cognition and motor skills
from birth throughout life
what does motor skill learning require
active central myelination (produces new OLs)
OPCs present densely in the hippocampus (learning site)
coexpress NG2 (Cspg4/Pdgfr) susceptible to hypoxia damage
signalling which causes myelination
communication via neuro-glial signalling molecules (gliotransmitters): 1)attract OPCs 2) proliferation 3) myelination
axon-OPC (direct) astrocytes (indirect)
NTs which affect myelination
adenosine (differentiation and myelination)
ATP
GABA (inhibits differentiation)
glutamate (promotes differentiation)
DA
ACh
BDNF promotes differentiation of myelin by stimulating the proliferation of OPCs
Growth factors which affect myelination
PDGF-AA/FGF2 (essential for OPC differentiation)
Wnt/BMP/Notch inhibit OPC differentiation
IGFI stimulates differentiation
Nrg1-Erb regulates myelination
decline in generation of OLs
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
developmental myelin pathologies
leukodystrophies (genetic cause)
cerebral palsy
both cause a loss of WM around the ventricles
myelin damage causes…
brain injury
infection
toxin
ischaemia/stroke
dementia
bipolar disease
ASD
schizophrenia
diseases which cause demyelination
MS
acute disseminated encephalomyelitis
Guilliane Barres Syndrome
symptoms of myelin loss
impaired vision (optic nerve is where demyelination is first seen)
impaired hearing
memory loss
loss of dexterity
who gets MS
1 in 1000 in the UK
females are more likely
age range: 15-50
mean onset: 28m 33f
prognosis: LT
5-10yrs reduced lifespan
what is MS
autoimmune disease
where the immune cells attack myelin
demyelination occurs in flares (relapses) then remyelination occurs (complete but thin and risk of failing)
genetic and environmental factors which cause MS
HLA class II gene (susceptibility gene)
associated gene: APOE/CNTF/osteopontin
environmental: EBV (after 15yrs) systemic infections
MS pathogenesis
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
physical MS pathogenesis
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
MS phases
preclinical
demyelination
remyelination
inactive/chronic demyelinating plaque
preclinical stage of MS
early phase lesion formed w/o clinical signs
depends on immune cells crossing BBB
triggers microglial activation without demyelination
microglia
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)
microglia activation states
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
4 patterns of MS lesions (demyelination)
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)
remyelination
thinner myelin and sheaths
requires adult OPCs (co-express NG2 - Cspg4) and Pdgfra
inactive/chronic demyelinating plaque
inside plaque there is a loss of myelin and OLs
plaques are acellular with few glia (small/fibrous astrocytes)
dense astrocytic gliosis
why does remyelination fail
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
Licensed MS drugs
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)
drugs in current trials to treat MS
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)
future therapies
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)
TRPA1
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
TRPA1 antagonists
FFA
increase Ca2+ increases amplitude of compound AP (measure CAPs in adult optic nerve - Lajoso et al)
prevents WM loss
