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Glia in health and
disease
Cell Mol Neurosci 8
Aim
 understand role of glial cells
 in
health
 astrocytes
 oligodendrocytes
 microglia
 and
disease
Diseases of nervous system…
Diseases of glia?
 MS
 ischemia
 epilepsy
Approaches
 epidemiology
 genetic
 anatomical
 animal models
Glia
 only 10% of cells in human brain are neurons
 Glia
 blood
vessels
 astrocytes
 oligodendrocytes
 microglia
Where do glial cells come from?
neuroectoderm
Cell fate
 NPC neuronal precursor cell
 transcription
factors
Cell fate
 transcription factors are regulated by (for
example)
 Leukemia
inhibitory factor (LIF) astrocyte
 Sonic hedgehog (Shh) oligodendrocyte
 Interact with timing
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
Summary
 Astrocytes
 metabolic
partner
 control blood supply
 regulate synaptic efficacy
In the PNS, Schwann cells
 Po protein
In the CNS, Oligodendrocytes …
differentiate…
…migrate
 PDGF promotes motility
 chemorepellent, netrin
 axonal following
 stop signals in ECM ??
plus actions of neurotransmitters
… myelinate and enstheath
 depends on axonal signals
 neurotransmitters
 NCAM
and
 N-cadherin
Summary
 Astrocytes
 metabolic
partner
 control blood supply
 regulate synaptic efficacy
 Oligodendrocytes and Schwann cells
 myelinate
axons
Microglia
 arise from macrophages outside CNS
 switch from resting to active state
 phagocytic
 migratory (chemotaxis)
Microglia
APC : antigen-presenting cell
Gliosis
 form scar tissue
 astrocytes
and microglia involved
 ischaemia → glu release → TNFa → …
 HIV infects microglia → release of
chemokines → …
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
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%
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 2006 gives relapse in 2016
 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
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
 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)
 express
metalloproteinases (e.g. TACE, TNFα-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
Glatiramer Acetate
 copaxone
 polymer molecular mimic of a region of
myelin basic protein
 may saturate HLA receptors
 FDA approved
Stem cell transplantation
 since 1995
 chemotherapy to kill T-cells
 toxicity up to 5%
 replace bone marrow to have fresh stem cells
Remyelination
 In a lesion, loss of myelin/axonal damage
major feature
 remyelination normally seen, but blocked by
glial scarring
Summary
 Astrocytes
 Oligodendrocytes and Schwann cells
 Microglia
 MS
 loss
of myelin over long time scale
 autoimmune disease
 EAE model suggests invasion of CNS by Tcells, followed by inflammatory cascade