MS Pathology and Animal Models

Question 1

Macro and micro MS pathology?

Answer 1

Atrophy: big ventricles, wide sulci

WM demyelin
GM demyelin
Remeyelin

inflam -> demylein-> axonal loss -> neurodegen

Commonly at optic nerve, midbrain (SNpc->PD), pons (fatal), cerebellum (ataxia) , s.cord

Question 2

Main cell involved in the destruction of myelin in MS

Answer 2

Macrophages

Question 3

Presence of macrophages are useful for identifying what in MS pathology?

Answer 3

The edge of the lesion

Question 4

Stains for MS?

Answer 4

Luxol Fast-blue

Oil Red: old lesion- the myelin has oxidised due to free radicals

Question 5

Explain why oligoclonal bands are present in MS

Answer 5

These are very specific antibodies (normally you should have a very varied repertoire)

NB: These antibodies are usually against myelin

Question 6

How MS causes progressive neurodegeneration?

Answer 6

• Axonal damage/loss -> neuronal loss [upstream effect] and synapse degradation [downstream] ]- because there is no propagation of action potentials
• Myelin loss -> axon isn’t protected -> increased Na+ channel expression (normally inhibited by myelin} -> more Na+ inside axon -> ionic imbalance -> can’t produce ATP -> ATP exhaustion -> metabolic problems
• Ca2+ getting in (whilst we try to get Na+ out of the axon) -> calcium-dependent pathways e.g. calpain -> cell death

Question 7

Relationship between axonal loss and severity of MS symptoms

Answer 7

More axonal loss = more severe symptoms

Question 8

Features of pathological axons in MS?

Answer 8

APP deposition and end bulbs

Question 9

Features of white matter inflammation VS grey matter inflammation

Answer 9

White matter: mainly perivascular in parenchyma; T and B cells

Grey matter: infiltration mainly in the meninges; less T and B cells

Question 10

In grey matter inflammation, what structures surround the lesions?

Answer 10

Lymphoid follicles

Question 11

Relationship between lymphoid follicles and grey matter degeneration?

Answer 11

More lymphoid follicles seem to be associated with a greater loss of neurons and a worse progression of the disease

TLS -> meningeal inflammation -> GM pathology

Meningeal inflammation -> more cortical pathology, disease progression, total demyelination, activated microglia, pro-infl chemokines

Question 12

Main animal models in use for MS?

Answer 12

• Experimental Autoimmune Encephalomyelitis (EAE)
• Theiler’s Murine Encephalomyelitis Virus (TMEV)
• Cuprizone-induced MS
• Lysolecithin-induced MS

Question 13

Describe Experimental Autoimmune Encephalomyelitis (EAE)

Answer 13

• Generation of myelin-specific autoimmune T cells.
  Immunisation of animals (rodents, primates) with myelin antigens in adjuvant.
• CD4+ T cells.
• Th17 and Th1.
• Depending on antigen used and mouse/rat strain we have different models of MS

Question 14

Describe passive Experimental Autoimmune Encephalomyelitis (EAE)

Answer 14

transfer of myelin-specific T cells into WT/Rag-/- mice

RAG = recombination activation gene

Question 15

Evaluate how useful Experimental Autoimmune Encephalomyelitis (EAE) is as a model for MS

Answer 15

Good model to study autoimmunity, not so much MS

Short- no remyelination
No relapses
Mainly white matter

Question 16

Describe Theiler’s Murine Encephalomyelitis Virus (TMEV)

Answer 16

• a virus used in mouse models of MS as it induces virally induced paralysis and encephalomyelitis
• axonal damage precedes demyelination (opposite to EAE/MS)

infection -> neurodegradation -> inflammation -> demyelination -> axonal/neuron loss

Question 17

Describe cuprizone

Answer 17

It is a copper chelator

• > oligodendrocyte cell death -> demyelination
• > activation of astrocytes and microglia -> inflammation

Question 18

Describe the events following cuprizone removal

Answer 18

OPCs -> new oligodendrocytes -> remyelination (this happens after cuprizone removal)

Question 19

Describe the advantages of using cuprizone as a model for MS

Answer 19

Good model for demyelination and remyelination

possibly good for studying mitochondrial dysfunction in MS

Question 20

Describe lysolecithin

Answer 20

• Activates phospholipase A2
• direct toxicity to myelin sheath (lipid degradation) -> rapid neuronal demyelination w/ intact oligodendrocytes
• no axonal damage
• leukocyte infiltration in demyelinated areas -> repair?

Question 21

Evaluate the use of lysolecithin as a model for MS

Answer 21

Better on young animal, showing complete remyelination after 5-6 weeks

Best model used to study remyelination and the role of the immune system in repair