Transcript Glia in health and disease

Glia in health and
disease
Aim
 understand role of glial cells
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
in health
 astrocytes
 oligodendrocytes
 microglia
and disease
Diseases of nervous system…
 Neurodegenerative
 Psychiatric

?developmental disorders
Diseases of glia?
 MS
 ischemia
 epilepsy
Approaches
 symptoms

something's – wrong
 anatomical
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post mortem
MRI
 epidemiology
 genetic
 animal models
Now onto: what do we know about healthy glia?
Glia
 only 10% of cells in human brain are neurons


Glia
blood vessels
 astrocytes
 oligodendrocytes
 microglia
Where do glial cells come from?
neuroectoderm
Astrocytes
polarised capillary-neuron
Metabolic partners
 take up glutamate down Na gradient
astrocyte
BV
Metabolic partners
 Na into Acyte stimulates energy metabolism
Metabolic partners
 neurons need lactate not glucose
 stimulate energy and glu back to neuron
Calcium waves
 activity dependent and spontaneous
 regulate “feet” on capillary
 release glu on neuron
bafilomycin blocks
synaptic transmission
Glutamate release
 high intracellular Ca leads to glu release

from lysosomes (?by exocytosis)
 role in strokes
Summary
 Astrocytes
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metabolic partner
control blood supply
regulate synaptic efficacy
axonal/synaptic outgrowth
Now onto: myelination
In the PNS, Schwann cells
 Po protein
In the CNS, Oligodendrocytes …
differentiate…
…migrate
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PDGF promotes motility
chemorepellent, netrin
axonal following
stop signals in ECM ??
plus actions of neurotransmitters
… myelinate and enstheath
 depends on axonal signals
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neurotransmitters
NCAM and
N-cadherin
Summary
 Astrocytes




metabolic partner
control blood supply
regulate synaptic efficacy
axonal/synaptic outgrowth
 Oligodendrocytes and Schwann cells

myelinate axons
Now onto: a third kind of glial cell: microglia
Microglia
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arise from macrophages outside CNS
switch from resting to active state
phagocytic
migratory (chemotaxis)
Microglia
APC : antigen-presenting cell
Gliosis
 form scar tissue
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astrocytes and microglia involved
ischaemia → glu release → TNFa → …
HIV infects microglia → release of chemokines → …
Summary
 Astrocytes
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metabolic partner
control blood supply
regulate synaptic efficacy
 Oligodendrocytes and Schwann cells

myelinate axons
 Microglia


immune elements of CNS
with astrocytes generate gliosis
Now onto: what happens in MS ?
MS
 Multiple sclerosis
 demyelinating disease

CNS
 recognised by Jean Martin Charcot in 1868
 symptoms
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initally weak movement, blurred vision
later bladder dysfunction, fatigue
 relapses in 85%
 IgG levels high
MS Lesions
 blue: myelin dye
 brown HLA antibody (marks MHC microglia)
 NAWM – normal appearing
white matter
Loss of myelin from OL
A: signals in white matter
B: lesions in corpus callosum
relapses associated with new lesions
Long time scale
 lesion in 2008 gives relapse in 2018
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anti-inflammatory treatments
over 2-3 years interferon reduced # people who had second
attack by ~30%
 15 years after diagnosis
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< 20% not affected in daily living
60 % need assisted walking
75% not employed
Epidemiology
1.2 : 1000 – in UK about 85000 people are affected
Genetics
 identical twins 20-30%
 fraternal same-sex twins 2-5%
 African Americans less susceptible than Caucasian
Americans
 HLA-DRB1 gene on chromosome 6p21
Environmental factors
 may have protein like myelin
 Chlamydia pneumoniae

in vitro infects microglial cells, astrocytes and neuronal
cells [was not replicated]
 Epstein-Barr virus as child

no causative explanation
 Sunlight (vitamin D), solvents, pollution,
temperature, rainfall….
Animal model
 experimental allergic (or autoimmune)
encephalomyelitis (EAE) (1935)
 lymphocytes cross blood-brain-barrier (BBB)
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express metalloproteinases (e.g. TACE, TNF-α-converting
enzyme)
b-interferon blocks metalloproteinases
destroys membranes and allows more cells through BBB
T-cells activated by myelin
 secrete cytokines ….
Suggested model of MS
How can we treat MS?
b-interferon-1B
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g-interferon levels go up just before relapses
b-interferon inhibits g-interferon
FDA approved
reduced relapses from 69% of patients in 2 years to
55%
Glatiramer Acetate
 copaxone
 polymer molecular mimic of a region of myelin
basic protein
 may saturate HLA receptors
 FDA approved
Choosing the right drug…
 Is an expensive business: since ~2002, 5583 patients
received interferon/glatiramer costing £350M
 NICE recommended … should not be used in NHS
because of doubts about their effectiveness and high price
 MS Society etc. applied pressure for these drugs to be
available
 Dept of Health created trial
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cost £8000/patient/annum (+15% for extra nurses)
cost to be reduced if quality of life not satisfactory
MS Society withdrew support in 2009 when results were
unsatisfactory
 MS patients got high % of NHS budget and extra nurses
Natalizumab
 trade name Tysabri (£15k /annum / patient)
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http://news.bbc.co.uk/1/hi/wales/7928456.stm
humanized monoclonal antibody
against the cellular adhesion molecule α4-integrin
prevent cells crossing blood-brain barrier
associated with PML (inflammation of white matter)

progressive multifocal leukoencephalopathy
New drugs ?
 oral drugs
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immunosuppressive
 Fingolimod
• Phase III trials (Oct. 2010)
cladribine
 NICE expected to recommend in Aug 2011 ?
Are we dealing with the right problem ?
Remyelination
 In a lesion, loss of myelin/axonal damage major
feature
 remyelination normally seen, but blocked by glial
scarring
Rat model
(ethidium
bromide)
Remyelination…
 red: demyelination
 blue remyelination
 very variable between
patients
What affects remyelination?
 lack of OPCs ?
 signalling?
in animal models, critical failure is due to macrophages not clearing myelin debris
which contains inhibitors of differentiation.
Stem cell transplantation
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since 1995
chemotherapy to kill T-cells
transplant-related mortality up to 5%
replace bone marrow to have fresh stem cells
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http://news.bbc.co.uk/1/hi/health/7858559.stm
Summary
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Astrocytes
Oligodendrocytes and Schwann cells
Microglia
MS
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loss of myelin over long time scale
autoimmune disease
EAE model suggests invasion of CNS by T-cells, followed
by inflammatory cascade
No effective treatment ????
 demyelination or remyelination ???