Multiple sclerosis Flashcards
What are the neurodevelopmental origins of glial cells?
ASTROCYTES and OLIGODENDROCYTES: COMMON MULTIPOTENT NEURAL STEM
CELL MICROGLIA: non-neural, derived from peripheral myeloid cells. They are macrophages which enter the brain prior to birth and remain there after BBB forms.
What is the structure and function of the cerebellum?
It controls movement.
Purkinje fibres - intergrate lots of information from many inputs to dendritic tree. One output through the axon.
Berghman glial cells in green next to purkinje fibre - it’s a type of astrocyte partnered with purkinje fibres. 3-5 berghman glial cells for 1 purkinje fibre. Berghman astrocytes take up glutamate and potassium
What are the main 7 functions of glial cells ?
- Developmental Neuro- and gliogenesis. Neuronal path finding. Synaptogenesis. 2. Structural. Astroglia form the scaffold of the nervous system, thus defining the functional architecture of the brain and spinal cord.
- Nutrition. Providing energy substrates for neurones. Formation of the glial–vascular interface. Regulation of cerebral microcirculation
- Homeostatic: Control of the CNS microenvironment, Regulation of extracellular K+, neurotransmitters (particularly glutamate - if it builds up it causes excitotoxicity). Collecting neuronal waste.
- Myelination - Oligodendrocytes. making myelin is a full time job.
- Phacocytosis and Immune Functions – Microglia
- Injury & Repair Glial Scar formation – ALL GLIA Repair and form scars
What is the structure and function of myelin?
fatty insulating layer made by oligodendrocytes in the CNS (schwann cells in PNS)
concentric lamellae wrap around the axon, extruding the cytoplasm between the bilipid membranes to form many insulating layer. consecutive sheaths are separated by nodes of ranvier. Tight junctions formed between myelin and axon cause segmented areas. This forced sodium channels into high concentrations in the node of ranvier, allowing AP to be generated.
Enables rapid axonal electrical conduction via saltatory conduction
What are the main compositional elements of myelin?
- Cholesterol (27%). Diet requires cholesterol for continual regeneration of myelin. Especially required during development - breast milk. Astrocytes take up cholesterol from blood, convert to APOE and give it to all other brain cells so they can synthesis APOE. Oligodendrocytes are very large hence they have the largest requirement for cholesterol.
- Phospholipids
glycosphingolipids (GSLs; 31%) - required for cellular recognition of oligodendrocytes. KO results in myelin unravelling at nodes of ranvier. Neurodegeneration follows.
Proteins - adherence of myelin sheath between layers and to the axon.
Which protein interactions mediate axon - myelin binding?
MAG, myelin associated glycoprotein
Which proteins mediate myelin-myelin binding?
They adhere layers of the myelin sheath so that it does not unravel.
- *Myelin Basic Protein (MBP) - cytoplasmic face.** deletion of the MBP gene results in myelin disruption
- *Proteolipid Protein (PLP) - extracellular face.** KO of PLP gene initially causes myelin unravelling causing shakiness in mice due to improper AP conduction. However after a month, axons began to degenerate. Correct myelination is critical for axonal integrity and survival.
What is the most important cell surface protein of oligodendrocytes
- myelin oligodendrocyte protein. serves as an antigen, becoming attacked by autoimmune defences in MS.
What is an important metabolic function of oligodendrocytes?
They supply axons with energy by lactate shuttle using glucose given to them by astrocytes. Astrocytes also directly supply axons.
How are oligodendrocytes generated?
They are continually generated throughout life from oligodendrocyte progenitor cells, which divide asymetrically to produce 1 daughter cell (oligodenrocyte precursor cell) and another progenitor - so stores are never depleted.
Why does white matter begin to shrink in older age?
Oligodendrocyte progenitor cells may become less capable of regenerating new ones. This begins from age 50 and is associated with cognitive decline.
What are the types of MS?
Primary progressive is a gradual loss of myelin beginning from the outset with no improvement from an early age until death. RARE - 10%
Relapse-remitting accounts for 90% of cases, where myelin is lost and then restored.
At age 50, for about 60% of R-R MS cases, it develops into Secondary progressive. This occurs when relapse-remittance becomes super imposed over normal ageing losses in myelin. The brain prominently shrinks due to neurodegenaration.
What are the early signs of MS?
Symptoms depedent on the site of demylination and degeneration - which often is very small.
Optical nerves are the usually the first site of degenaration - most syndromes begin with flashing lights due to lack of information from retina to the brain. Tingling fingers is also an early symptom. Any symptoms are relatively late stage because demyelination has already occured.
Stiffness or slight cognitive slowness do usually begin before this but are not normally the reasons for presenting to the clinic.
What are the four stages of MS?
Preclinical -
Demyelination -
Remyelination -
Inactive/Chronic Demyelinating plaque
Preclinical MS
- Early phase of lesion formation without clinical signs
- Depends on immune cells crossing the BBB and getting into the CNS
- Triggers microglial activation without demyelination
- The pathology in early stages of MS is based largely on animal studies
What are the two phenotypes of microglia?
M1 (‘proinflammatory’, associated with acute infection). This phenotype is key to the relapse phase where there is rapid demyelination
M2 (‘anti-inflammatory’ associated with tissue remodelling). This phenotype is key to the remittance phase, where damaged myelin is phagocytosed and new myelin becomes regenerated - microglia are required for this.
This is an oversimplification - there are many intermediate phases.
Chronic Inactive Demyelinating Plaque
Whilst much myelin does undergo regeneration and axons can be salvaged, over time there will become regions of chronically unmyelinated axons. The axons are degenerated and all that remains is an astrocytic scar.
