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

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

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 → 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

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

B: lesions in corpus callosumA: signals in white matter

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,

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

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

T-cells, followed by inflammatory cascade