glia in health and disease
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Glia in health and disease. Aim. understand role of glial cells in health astrocytes oligodendrocytes microglia and disease. Neurodegenerative. Psychiatric ?developmental disorders. Diseases of nervous system…. Diseases of glia?. MS ischemia epilepsy. Approaches. symptoms - PowerPoint PPT PresentationTRANSCRIPT
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Glia in health and disease
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Aim understand role of glial cells
in health astrocytes oligodendrocytes microglia
and disease
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Diseases of nervous system…
Neurodegenerative Psychiatric ?developmental
disorders
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Diseases of glia? MS ischemia epilepsy
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Approaches symptoms
something's – wrong
anatomical post mortem MRI
epidemiology genetic animal models
Now onto: what do we know about healthy glia?
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Glia only 10% of cells in human brain are neurons
Glia blood vessels
astrocytes oligodendrocytes microglia
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Where do glial cells come from?
neuroectoderm
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Astrocytespolarised capillary-neuron
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Metabolic partners take up glutamate down Na gradient
astrocyte
BV
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Metabolic partners Na into Acyte stimulates energy metabolism
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Metabolic partners neurons need lactate not glucose stimulate energy and glu back to neuron
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Calcium waves activity dependent and spontaneous regulate “feet” on capillary release glu on neuron
bafilomycin blocks synaptic transmission
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Glutamate release high intracellular Ca leads to glu release
from lysosomes (?by exocytosis)
role in strokes
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Summary Astrocytes
metabolic partner control blood supply regulate synaptic efficacy axonal/synaptic outgrowth
Now onto: myelination
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In the PNS, Schwann cells Po protein
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In the CNS, Oligodendrocytes …
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differentiate…
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…migrate PDGF promotes motility chemorepellent, netrin axonal following stop signals in ECM ??
plus actions of neurotransmitters
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… myelinate and enstheath
depends on axonal signals neurotransmitters NCAM and N-cadherin
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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
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Microglia arise from macrophages outside CNS switch from resting to active state phagocytic migratory (chemotaxis)
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Microglia
APC : antigen-presenting cell
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Gliosis form scar tissue
astrocytes and microglia involved ischaemia → glu release → TNF → … HIV infects microglia → release of chemokines → …
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Summary Astrocytes
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 ?
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MS Multiple sclerosis demyelinating disease
CNS
recognised by Jean Martin Charcot in 1868 symptoms
initally weak movement, blurred vision later bladder dysfunction, fatigue
relapses in 85% IgG levels high
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MS Lesions blue: myelin dye brown HLA antibody (marks MHC microglia)
NAWM – normal appearing white matter
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Loss of myelin from OL
B: lesions in corpus callosumA: signals in white matter
relapses associated with new lesions
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Long time scale lesion in 2008 gives relapse in 2018
anti-inflammatory treatments over 2-3 years interferon reduced # people who
had second attack by ~30%
15 years after diagnosis < 20% not affected in daily living 60 % need assisted walking 75% not employed
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Epidemiology
1.2 : 1000 – in UK about 85000 people are affected
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Genetics identical twins 20-30% fraternal same-sex twins 2-5% African Americans less susceptible than
Caucasian Americans HLA-DRB1 gene on chromosome 6p21
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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….
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Animal model experimental allergic (or autoimmune)
encephalomyelitis (EAE) (1935) lymphocytes cross blood-brain-barrier (BBB)
express metalloproteinases (e.g. TACE, TNF-α-converting enzyme)
-interferon blocks metalloproteinases destroys membranes and allows more cells through
BBB T-cells activated by myelin
secrete cytokines ….
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Suggested model of MS
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How can we treat MS?
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-interferon-1B -interferon levels go up just before relapses -interferon inhibits -interferon FDA approved reduced relapses from 69% of patients in 2
years to 55%
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Glatiramer Acetate copaxone polymer molecular mimic of a region of
myelin basic protein may saturate HLA receptors FDA approved
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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 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
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Natalizumab trade name Tysabri (£15k /annum / patient)
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
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New drugs ? oral drugs
immunosuppressive Fingolimod
• Phase III trials (Oct. 2010) cladribine
NICE expected to recommend in Aug 2011 ?
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Are we dealing with the right problem ?
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Remyelination In a lesion, loss of myelin/axonal damage
major feature remyelination normally seen, but blocked by
glial scarring
Rat model (ethidium bromide)
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Remyelination… red: demyelination blue remyelination very variable between
patients
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What affects remyelination?
lack of OPCs ? signalling?
in animal models, critical failure is due to macrophages not clearing myelin debriswhich contains inhibitors of differentiation.
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Stem cell transplantation since 1995 chemotherapy to kill T-cells transplant-related mortality up to 5% replace bone marrow to have fresh stem cells
http://news.bbc.co.uk/1/hi/health/7858559.stm
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Summary Astrocytes Oligodendrocytes and Schwann cells Microglia MS
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 ???