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Glia in health and disease

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

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Glia in health and disease

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  1. Glia in health and disease

  2. Aim • understand role of glial cells • in health • astrocytes • oligodendrocytes • microglia • and disease

  3. Neurodegenerative Psychiatric ?developmental disorders Diseases of nervous system…

  4. Diseases of glia? • MS • ischemia • epilepsy

  5. Approaches • symptoms • something's – wrong • anatomical • post mortem • MRI • epidemiology • genetic • animal models Now onto: what do we know about healthy glia?

  6. Glia • only 10% of cells in human brain are neurons • Glia • blood vessels • astrocytes • oligodendrocytes • microglia

  7. Where do glial cells come from? neuroectoderm

  8. Astrocytes polarised capillary-neuron

  9. Metabolic partners • take up glutamate down Na gradient astrocyte BV

  10. Metabolic partners • Na into Acyte stimulates energy metabolism

  11. Metabolic partners • neurons need lactate not glucose • stimulate energy and glu back to neuron

  12. Calcium waves • activity dependent and spontaneous • regulate “feet” on capillary • release glu on neuron bafilomycin blocks synaptic transmission

  13. Glutamate release • high intracellular Ca leads to glu release • from lysosomes (?by exocytosis) • role in strokes

  14. Summary • Astrocytes • metabolic partner • control blood supply • regulate synaptic efficacy • axonal/synaptic outgrowth Now onto: myelination

  15. In the PNS, Schwann cells • Po protein

  16. In the CNS, Oligodendrocytes …

  17. differentiate…

  18. …migrate • PDGF promotes motility • chemorepellent, netrin • axonal following • stop signals in ECM ?? • plus actions of neurotransmitters

  19. … myelinate and enstheath • depends on axonal signals • neurotransmitters • NCAM and • N-cadherin

  20. 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

  21. Microglia • arise from macrophages outside CNS • switch from resting to active state • phagocytic • migratory (chemotaxis)

  22. Microglia APC : antigen-presenting cell

  23. Gliosis • form scar tissue • astrocytes and microglia involved • ischaemia → glu release → TNFa → … • HIV infects microglia → release of chemokines → …

  24. 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 ?

  25. 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

  26. blue: myelin dye brown HLA antibody (marks MHC microglia) NAWM – normal appearing white matter MS Lesions

  27. Loss of myelin from OL A: signals in white matter B: lesions in corpus callosum relapses associated with new lesions

  28. 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

  29. Epidemiology 1.2 : 1000 – in UK about 85000 people are affected

  30. Genetics • identical twins 20-30% • fraternal same-sex twins 2-5% • African Americans less susceptible than Caucasian Americans • HLA-DRB1 gene on chromosome 6p21

  31. 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….

  32. Animal model • experimental allergic (or autoimmune) encephalomyelitis (EAE) (1935) • lymphocytes cross blood-brain-barrier (BBB) • 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 ….

  33. Suggested model of MS

  34. How can we treat MS?

  35. 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%

  36. Glatiramer Acetate • copaxone • polymer molecular mimic of a region of myelin basic protein • may saturate HLA receptors • FDA approved

  37. 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

  38. 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

  39. New drugs ? • oral drugs • immunosuppressive • Fingolimod • Phase III trials (Oct. 2010) • cladribine • NICE expected to recommend in Aug 2011 ?

  40. Are we dealing with the right problem ?

  41. Remyelination • In a lesion, loss of myelin/axonal damage major feature • remyelination normally seen, but blocked by glial scarring Rat model (ethidium bromide)

  42. red: demyelination blue remyelination very variable between patients Remyelination…

  43. lack of OPCs ? signalling? What affects remyelination? in animal models, critical failure is due to macrophages not clearing myelin debriswhich contains inhibitors of differentiation.

  44. 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

  45. 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 ???

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