L6 - Glia and Multiple Sclerosis Flashcards
What proportion of brain is neurons
10%
What other cells make up the brain?
Glia blood vessel astrocytes oligodendrocytes microglia
When do glial cells first come about?
Last, after the neurogenesis of neurons
What do astrocytes do?
Takes glucose from capillary and gives it to neuron
What do astrocytes do at the synaptic cleft?
Takes up glutamate using proton motive force and then gives it back to presynapse
Why does glycolysis have to occur in astrocytes?
Used for Na ATPase and proton motive force
What happens to the glucose that goes through the astrocyte destined for the neurons and why?
Glycolysis makes lactate
Neurons cannot use glucose very well
How is the glutamate transferred back into the neuron?
Using ATP to turn it into glutamine then goes in
What does high Ca in astrocytes do?
Leads to glutamate release
What happens to astrocytes during a stroke?
Release large amounts of glutamate from lysosomes and into cleft
Activate neurons and get cytotoxix stress
What do oligocendrocytes do?
Wrap up axons in myelin sheath
What are the components of the myelin sheath?
Proteolipid proteins
Myelin basic protein
How do oligodentrocytes migrate?
PDGF promotes motility
Signals are chemorepellent eg netrin tell them to go
Stop signals in ECM
WHere do microglia arise from?
macrophages outside the CNS
What are are the features of microglia?
Tidy up any damage
Phagocytic
Antigen presenting cells
What is gliosis?
Astrocytes and microglia forming scar tissue
How are microglia led to the place of damage?
TNFa
Why is HIV such a bad disease?
infects microglia
What are the features of MS?
Demylenating disease of the CNS
Symptoms - weak movement, blurred vision (optic nerve), fatigue
IgG levels high
What does a scan of aNn MS patient show?
Lesions where white matter has been destroyed
Why is the risk of MS higher in US, UK, Central Europe, NZ than in equatorial regions?
Hypothesis on sunlight exposure or day length
What kind of genes are generally mutated in MS?
T cell related genes
What are the environment factors that may be important in MS?
Possibly associated with virus’
Sunlight, solvents, pollution, temp
What is the t cell model for MS?
T cell invasion and inflammation
Gobble up oligodendrocytes
How could oxidative stress possibly cause MS?
Influx of Na ions, so mitochondria must produce a lot of ATP, and so produce oxidative stress
Cells degenerate, let in more Ca, cascades to more damage
How can cannabis be used for MS?
Relieves muscle stiffness, body pain, muscle spasms
What drugs could help with MS?
B-interferon-1B
Glatiramer acetate
Natalizumab
How is B-interferon-1B involved in MS?
Levels go up before relapse
Inhibits gamma-interferon
What is the success of B-interferon?
Reduces relapses from 69% of patients in 2 years to 55%
How does glatiramer acetate help MS?
Molecular mimic of a region of myelin basic protein so HLA binds to that
Whats the problem with MS drugs?
Very expensive
Not very effective
What were the problems with natalizumab?
Had inflammation of white matter in some patients because of John Cunningham virus
What are some recent drugs for MS?
Oral - fingolimod - blocks lymphocyte migration by internalising receptor
Dimethyl fumarate - counters oxidative stress in Nrf2 pathway
What is Alemtuzumab?
Drug that affects migration of lymphocytes
Monoclonal antibody
Anti CD52 a surface glycoprotein
Reduces TNF-a, IL-6
Whats stopping oligodendrocytes repairing the myelination?
Blocked by glial scarring
What do we think affects remyelination?
Macrophages not clearing myelin debris which contains inhibitors of differentiation such as wnt signals
