Glia in health and disease

Aim understand role of glial cells

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 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

Astrocytespolarised 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

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 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 axonal/synaptic outgrowth

Oligodendrocytes and Schwann cells myelinate axons

Now onto: a third kind of glial cell: microglia

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 → TNF → … 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

Now onto: what happens in MS ?

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

MS Lesions blue: myelin dye brown HLA antibody (marks MHC microglia)

NAWM – normal appearing white matter

Loss of myelin from OL

B: lesions in corpus callosumA: signals in white matter

relapses associated with new lesions

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

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)

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 ….

Suggested model of MS

How can we treat MS?

-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%

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 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)

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

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 debriswhich contains inhibitors of differentiation.

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

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 ???