Demyelinating Diseases Flashcards
Astrocytes
Formation of the BBB
(Ischaemia = activation, down-reg tight junctions = increased permeability of leukocytes)
Tripartate synapses = Anja Teschemacher
Monitor neuronal activity
Oligodendrocytes
CNS
1 oligodendrocyte can myelinate multiple axons - wraps processes (myelin sheath)
Contains NT receptors = CONTROVERSIAL
- Immunogold staining = mature oligodendrocytes - expresss GluN1/N3 NMDARs
BUT - No GluA2 = therefore do not respond to glutamate
- Glycine is sufficient for basal activation = why is there not high NMDAR activity?
Resolve = alternative immunocytochemical approach with an alternative validated AB
- not immunogold = <15-30 nm away = low sensitivity
Schwann cells
PNS
1:1 Schwann:neurone
Guillan-Bare syndrome = autoimmune disorder which attacks Schwann cells; get IgG in plasma!
Demyelinating disorders (DD)
DD = a group of diseases which involve damage and destruction of myelin sheaths that surround nerve fibres
- The axons of the neurones may also become damaged (they become exposed)
- Unknown aetiology
Includes = MS (auto-immune), PVL, Guillain-Bare syndrome (auto-immune; PNS)
Occur where myelin is normally present = more myeline, higher chance of being affected
ie. Optic nerve = highly myelinated - optic neuritis is a common syndrome
Demyelination is variable occurring on the site
See plaques of demyelination on MRI
Multiple Sclerosis
Symptoms
Risk Factors
Slowly progressive CNS disorder characterised by plaques of demyelination in the brain/spinal cord, resulting in multiple + varied neurological symptoms, usually with remissions + relapses
Symptoms are varied - multiple sites where demyelintion can occur therefore symptoms are complex + diverse
- Optic neuritis = optic nerves are highly myelinated (rich source of oligodendrocytes; long pathways from eyes to visual cortex, any demyelination occurring could cause any visual effects) - could get scotoma (blind spot)
- Paresthesias in one or more extremities = abnormal tingling sensations caused by damage to peripheral nerves
- Scanning speech
- Deep reflexes are increased
- Superficial reflexes are absent/diminished
= Many are transient - high level of recovery!
RISKS
Northern hemisphere = increased risk due to vitamin D deficiency (risk level dependent on where you live for the first 8 years of life)
GENETICS = cause is known GWAS = identified SNPs + CNVs involved in immune function
MS Pathology + diagnosis
Plaques of demyelination
Perivascular inflammation
Common islands of plaques =
- Periventriclar region (ABs coming from the CSF) = euphoria, poor memory and concentration, dementia, acute psychiatric disorder
- Optic nerves; can produce scotomas
- Spinal cord
- Subcortical white matter
- Cortical white matter
- Brainstem = life-threatening
Diagnosis
- MRI = see plaques - areas of increased signal (see lesions) - particularly in the periventricular region (ABs coming from the CSF)
- Oligoclonal bands = IgG bands present in the CSF (but not blood plasma; if plasma, could be indicative of Guillain-Bare syndrome)
- may be absent early on in the disease
Forms of MS
RRMS = Remitting, relapsing MS ~ 80%
- Relapsing (attacks) followed by remission (remyelination occurring)
SPMS = Secondary, progressive MS - a stage of MS which often occurs after RRMS (with/without relapses)
Symptoms worsen over time, with/without the occurrence of remissions/relapses
PPMS = Primary, progressive MS – rare ~ 15%
Steadily worsening conditions
PRMS = Primary, remitting MS very rare ~ 5%
Progressive conditions with acute remissions without relapses
Treatments
Interferon = naturally occurring anti-inflammatory cytokine
- Increases regulatory T-cells; decreases pro-inflammatory cells
- Decreases permeability of the BBB
Methylprodisone = glucocorticoid; suppresses inflammation
Control muscle tone/spasticity = Baclofen (GABAb agonist) + Botox (cleave SNARE complex of nAChRs)
Novel targets
P2X4 = diverse pro- and anti-inflammatory functions deepening on cellular location
- Can release BDNF when activated on macrophages = cause neuronal excitability by collapsing Cl- gradient
GPR17 receptor = potential target to implement repair and remyelination in neurodegeneration; transiently expressed on early OPCs + down-regulated to allow cells to mature
Primary = Autoimmune
B cells = produce antibodies against myeline
CONTROVERSIAL - produce ABs against GIRK channels - not enough supporting evidence
T cells = produce free radicals + cytokines
Free radical production = increased GluA3 translation; oxidative damage, histone phosphorylation, lipid perioxidation
- T cells activated in the PNS via antigens leaking through the BBB
- BBB permeability dysregulated via astrocytic activation = down-regulation of tight junction proteins
- Activated T cells enter CNS via compromised BBB where they secrete pro-inflammatory cytokines + chemokines
Healthy = regulatory T-cells which oppose inflammatory effects; down-regulate the activity of pro-inflammatory mediators which allows for repair + recovery MS = deficits of regulatory T-cell function; increased inflammation/autoimmune = results in neurodegeneration
Secondary = Excitotoxicity
CONTROVERSIAL = whether mature oligonucleotides contain GluN1/N3 unique NMDARs on the myelin sheath
FOR - identified via immunogold staining
BUT controversial because GluN1/N3 does not need glutamate binding (GluN2), just glycine (GluN1) - basal glycine should be enough to excite - surely they are therefore being basally excited?
RESOLVE = alternative immunocytochemical approach with a different, highly validated AB
Increased extracellular glutamate due to:
- Down-regulation of EAAT1/2 (activated P2X7-macrophages, release interleukin)
- Cytokines up-regulate VGSCs = increased depolarisation; increased glutamate release
- Inflammatory cells release glutamate; activated T cells release glutamate, glutamate activates T cells = positive feedback loop
- Decreased enzymatic activity of glutamine synthethase
Remyelination
New OPCs (SVZ) are recruited to an area of demyelination = recruited to differentiate and restore myelin sheaths to axons
OPC activation via mitogens, GFs, chemokines etc. released from glial cells
ASTROCYTES
- Release GDGF = inhibit premature oligodendrocyte differentiation
- Physical contact via integrins = facilitates oligodendrocyte maturation
- Help to increase the thickness of the sheath
BUT astrocytes are also responsible for increased BBB permeability (down-regulate tight junction proteins) and they also release cytokines (increase VGSCs)
Remyelination should recapitulate developmental myelination but inflamed and activated milieu surrounding the lesion compromises + limits the efficacy of the remyelination process - therefore remyelination is not as thick as before
Periventricular Leukomalacia (PVL)
Ischaemia of the periventricular area leading to tissue softening (malacia)
24 - 32 weeks = oligodendrocytes are highly vulnerable due to NT profile - vulnerable developmental window; during migration/early differentiation
Focal necrotic component = deep in periventricular white matter; can evolve to form multiple cystic lesions
- Visualise with ultrasound
Diffuse component (oligodendrocyte specific component) = astriogliosis + microgliosis
- Decrease in pre-OLs and an increase in OPCs
- OPCs do not have the full capacity for full myelination = produce hypomyelination causing ventromegaly
Lineage: OL progenitor (OPC) --> Pre OL --> Immature OL --> Mature OP
Pre-OP soma = highly Ca-permeable NMDAR/AMPARs and mGluR5 (Gq)
mGluR5 = highly expressed in OPCs; down-regulate as they differentiate into mature oligodendrocytes - act as some protection during OGD (stimulate astrocytic glutamate uptake BUT the cytodestructive effects of inotropic glutamate Rs outweighs cytoprotective effects of mGluR5)
PVL Animal Model
Rodent on P7
Carotid ligation followed by hypoxia for 1 hour = selective white matter injury
BUT
- Rodent = 10% white matter whereas humans = 40% white matter
therefore not very representative
