Glia in health and disease

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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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Astrocytes
polarised 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 ? TNFa ?
• 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 callosum
A 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
• lt 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-a-converting enzyme)
• b-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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b-interferon-1B

• 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

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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
  a4-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 ???