MS Pathology and Animal Models Flashcards
Macro and micro MS pathology?
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
Main cell involved in the destruction of myelin in MS
Macrophages
Presence of macrophages are useful for identifying what in MS pathology?
The edge of the lesion
Stains for MS?
Luxol Fast-blue
Oil Red: old lesion- the myelin has oxidised due to free radicals
Explain why oligoclonal bands are present in MS
These are very specific antibodies (normally you should have a very varied repertoire)
NB: These antibodies are usually against myelin
How MS causes progressive neurodegeneration?
- 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
Relationship between axonal loss and severity of MS symptoms
More axonal loss = more severe symptoms
Features of pathological axons in MS?
APP deposition and end bulbs
Features of white matter inflammation VS grey matter inflammation
White matter: mainly perivascular in parenchyma; T and B cells
Grey matter: infiltration mainly in the meninges; less T and B cells
In grey matter inflammation, what structures surround the lesions?
Lymphoid follicles
Relationship between lymphoid follicles and grey matter degeneration?
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
Main animal models in use for MS?
- Experimental Autoimmune Encephalomyelitis (EAE)
- Theiler’s Murine Encephalomyelitis Virus (TMEV)
- Cuprizone-induced MS
- Lysolecithin-induced MS
Describe Experimental Autoimmune Encephalomyelitis (EAE)
- 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
Describe passive Experimental Autoimmune Encephalomyelitis (EAE)
transfer of myelin-specific T cells into WT/Rag-/- mice
RAG = recombination activation gene
Evaluate how useful Experimental Autoimmune Encephalomyelitis (EAE) is as a model for MS
Good model to study autoimmunity, not so much MS
Short- no remyelination
No relapses
Mainly white matter
Describe Theiler’s Murine Encephalomyelitis Virus (TMEV)
- 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
Describe cuprizone
It is a copper chelator
- > oligodendrocyte cell death -> demyelination
- > activation of astrocytes and microglia -> inflammation
Describe the events following cuprizone removal
OPCs -> new oligodendrocytes -> remyelination (this happens after cuprizone removal)
Describe the advantages of using cuprizone as a model for MS
Good model for demyelination and remyelination
possibly good for studying mitochondrial dysfunction in MS
Describe lysolecithin
- 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?
Evaluate the use of lysolecithin as a model for MS
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
