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48 Cards in this Set
- Front
- Back
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What is MS? What is its PNS equivalent?
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An autoimmune demyelinating disease of the CNS. PNS equivalent: Charcot-Marie-Tooth disease, Guillian-Barre syndrome.
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What are the 2 types of MS?
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Relapsing-remitting, primary progressive.
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The symptoms of MS depend on the pathways lesioned. What does a spinal cord lesion cause? Optic nerve lesion? Cerebellar?
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Numbness and weakness, visual disturbances, ataxia and brainstem vertigo.
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Which Glial types are involved in MS? Which one especially?
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All. (Microglia, oligodendrocytes, astrocytes). Oligodendrocytes especially.
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What is the pathological hallmark of MS?
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White matter demyelination lesion, causing axonal degradation due to loss of myelin.
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Why are microglia important in MS?
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Because it is an autoimmune disease.
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What causes demyelination in MS?
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Adult oligodendrocyte progenitor cells.
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Give some features of microglia.
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Network of delicately ramified cells, distributed in regular mosaic patterns in the CNS, comprise 5% of cells in the brain. Phagocytotic and immune cells.
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What do microglia do at rest?
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They are never "resting" but "ramified" - continuously sampling the environment and are sensitive to the presence of ATP (purine), usually released as a result of neuronal damage.
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What happens after injury, inflammation, and immune insults?
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• Vascular macrophages can enter the brain
• Microglia become activated |
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What do activated microglia do?
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• regain macrophage-like status
• present antigen to T-cells • precipitate immune reactions |
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What are microglia strongly immunosuppressed by?
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• via neurokines liberated by neurons
• TGF made by astrocytes |
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Where are oligodendrocytes found? What is their relationship with axons?
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Only in the CNS. One cell myelinates multiple axons.
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How does myelination vary with life?
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Occurs throughout life in grey matter.
• Oligodendrocyte generation continues up to 50 years old in human cortex • Plasticity and growth • Loss and replacement of myelin |
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Name 3 facts about OPCs.
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Oligodendrocyte progenitor cells.
• A population of OPC’s persists in the adult CNS • Identified by expression of PDGF -alphaR and NG2 • Regenerate oligodendrocytes in MS |
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What is the myelin sheath? What does it facilitate? What it its composition? What are sheets separated by?
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• fatty insulating layer
• facilitates saltatory conduction • concentric lamellae wrap around the axon to form an insulating layer • along the axon consecutive myelin sheaths separated by nodes of Ranvier |
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How does myelination provide the massive computing power of the human brain?
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1. Great increase in nerve conduction velocity
2. Profound decrease in the size of nerves |
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How does AP propagation compare in myelinated and unmyelinated axons?
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It is far faster in myelinated axons. Without myelin, in order to keep conduction speed constant, the optic nerves would have to be 0.75m.
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What is the composition of myelin?
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Lipids – 70% dry weight
- provide myelin with its insulating properties Proteins – 30% dry weight - fuse and stabilise myelin lamellae - mediate membrane-membrane interactions - between myelin lamellae - between the axon and myelin |
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Name a main CNS myelin protein beginning with M. What are its characteristics?
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MBP, Myelin Basic Protein.
family of proteins with many isoforms; fusion of the cytoplasmic interface of the myelin lamellae; deletion of the MBP gene results in the loss of the major dense line |
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What is the other main CNS myelin protein?
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PLP, proteolipid protein. 50% of CNS myelin proteins, with two isoforms, PLP and DM-20; fuses the extracellular face of the myelin lamellae and forms the intraperiod line; spontaneous mutations of PLP gene results in unravelling of myelin (e.g. the jimpy (jp) mouse, myelin deficient (md) rats, and the shaking pup, and transgenic knock-out mice; absence of PLP/DM-20 also results in axonal degeneration (Griffiths et al., Science. 1998 Jun 5;280(5369):1610-3).
In humans, mutations affecting the plp gene cause Pelizaeus-Merzbacher disease (PMD), which is a severe, slowly progressive leukodystrophy of early-onset. |
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What is CNP?
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Cyclic nucleotide phosphodiesterase, an oligodendrocyte specific enzyme with uncertain function, but the absence of CNP results in axon degeneration, whereas myelin was unaltered in these mice.
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What is the lipid composition of myelin?
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Lipids – phospholipids, and the major components of myelin cholesterol (27%) and glycosphingolipids (GSLs; 31%)
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Name some GSLs specific to OLs. What are they used for?
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galactocerebrosides (GalC)
sulfated derivative sulfatide, recognized by the monoclonal antibody O4 Both used to identify Ols |
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Name 4 functions of GSLs.
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- Negative regulators of OL differentiation
- Lipid rafts - Neuron-glia interactions - Creation of domains along axons |
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What does the evidence from mice lacking PLP or CNP in oligodendrocytes show?
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The integrity of myelinated axons depends critically on oligodendrocytes.
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Name two other similar sounding myelin proteins.
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- MAG (myelin associated glycoprotein) – PNS and CNS - interactions between axon and myelin
- MOG (myelin oligodendrocyte glycoprotein) – CNS specific – main antigen in the animal model of MS (EAE– experimental autoimmune encephalomyelitis) |
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How are ODCs and axons linked?
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• Oligodendrocyte development is dependent on axons
• Axonal development is dependent on oligodendrocytes • Induction of nodes of Ranvier depends on oligodendrocytes • Loss of myelin leads to axon dysfunction: • demyelination in MS • degeneration in the absence of PLP, CNP or GalC • Axon degeneration leads to loss of oligodendrocytes |
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Give 3 points about axon loss in MS.
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• The loss of axons is a prominent feature of MS and animal models
• axonal damage may occur during the early stages of MS • may precede demyelination in some active plaques |
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What are the four essential neuron-supporting functions of astroctyes?
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• Injury and the glial scar
• Neurotransmitter removal • Potassium Uptake • Metabolic Support |
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What happens when CNS axons are injured?
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They do not regenerate - regrowth is inhibited by the glial scar. Made up of astrocytes, NG2-glia and myelin debris.
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Describe glutamate uptake by astrocytes.
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Glutamate-glutamine shuttle
• Glt1 specific to astrocytes • Glutamine Synthetase (GS) specific to astrocytes • Astrocytes recycle glutamate to glutamine, which they return to the presynaptic terminal |
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What does astrocytic glutamate uptake protect against?
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Excitotoxicity.
• High level of glutamate causes excitotoxicity – destruction of neurons. • The most common cause is ischemia during stroke. Lack of oxygen causes glutamate transporters to fail and glutamate accumulates. • Glutamate mediated excitoxicity also important in Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Alzheimer’s Disease (AD). |
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Name 3 pathological features of MS.
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• characterised by demyelinated plaques in white matter tracts of the brain and spinal cord
• usually starts as relapsing/remitting where periods of demyelination are followed by partial remyelination • but can become chronic progressive where demyelination becomes more widespread and patient deteriorates slowly with no remission |
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Name 4 phases of MS.
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- acute
- active chronic - inactive chronic - remyelinating/shadow plaques |
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What is the acute phase of MS?
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Early stage of lesion formation without any clinical signs. Characterised by microglial activation without demyelination. What we know of pathology in this stage is based largely on animal studies.
- Macrophages cross the BBB and form perivascular cuffs around blood vessels, they then migrate into the brain - Resident microglia become activated and release inflammatory cytokines - Leads to oedema, myelin swelling and damage to BBB |
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Name some cytokines and growth factors involved in MS.
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TNF-alpha, IFN-gamma, ILs, NO, PDGF-AA, FGF, CNTF, LIF.
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What happens in the active chronic phase?
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Myelin at the edges of active lesions is fragmented.
– large-scale demyelination, microglial/macrophage activation/infiltration, astrogliosis - defined pathologically by lesions packed with lipid-containing macrophages from phagocytosing myelin sheaths |
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What happens in the inactive chronic phase?
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• Within the plaque there is a massive loss of myelin and oligodendrocytes
• 0-2/mm2 compared to 300-400mm2 in normal brain white matter • Lipid stains show no evidence of recent myelin breakdown but some plaques may have lipid phagocytes • Myelin appears normal at the edges of quiescent lesions • Plaques are mainly acellular and the few glia present are mainly astrocytes which are small and fibrous • There is dense astrocytic gliosis This is where you get axonal degeneration. |
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What happens in the remyelinating phase?
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Remyelination is by OPCs.
Shadow plaques myelin stains show paler than normal areas of MS patients brain white matter EM shows thinner myelin sheaths around axons Can have demyelinated areas within remyelinated plaques, suggesting recurrent demyelination |
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Why does remyelination ultimately fail?
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OPCs appear 'abnormal' in MS lesions.
Astroglial scar formation • chronic plaques have a dense astroglial scar • inhibit remyelination The plaque environment • Lack of appropriate growth factors? • Presence of inhibitory factors? Lack of axonal signals • To generate oligodendrocytes, OPCs require appropriate growth factors and axon-derived signals |
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Describe a study on cnp.
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Lappe-Siefke 2003. In the absence of glial CNP, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.
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Describe an OPC study.
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Zawadzka 2010. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.
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What do active plaques contain?
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Areas of myelin breakdown, infiltration by inflammatory cells and collec- tions of lipid-containing macrophages that may stain for myelin proteins like myelin basic protein (MBP) or myelin-associated glycoprotein.
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What macrophage-like things do chronic plaques contain?
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Macrophage-like cells remain lipid-laden and are often called “foamy macrophages,” although they no longer contain immunoreactive myelin proteins.
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What is EAE? What are its pros/cons?
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Experimental allergic encephalomyelitis. Produced by immunisation against elements of myelin (e.g. MBP).
- Advantages: includes demyelination and partial remyelination, lesions distributed around bloody vessels. - Disadvantages: no specific AI antigen identified in MS, purely T cell response, failure of drug translation. |
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Describe a study on microglia in MS.
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Bo 1994. Tissue sections of brains from patients with multiple sclerosis (MS) and from control individuals were immunostained with MHC class II and glial or vascular endothelial cell antibodies and analyzed by confocal microscopy. MHC class II was abundant in and around actively demyelinating MS lesions and was detected on microglia, phagocytic macrophages, and perivascular macrophages. Astrocytes and vascular endothelial cells were MHC class II-negative. Changes in the size and shape of MHC class II-positive cells associated with MS lesions suggest that microglia transform into phagocytic macrophages, and that they are actively involved in demyelination. Many MHC class II-positive perivascular macrophages within MS lesions contained abundant intracellular MHC class II immunoreactivity; these cells may be involved in antigen presentation and in T cell activation.
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Describe a drugs trial for MS.
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Polman 2006. Double blind RCT of the alpha-4 integrin antagonist natalizumab. Modulates leucocyte adhesion and prevents infiltration across BBB. 92% fewer lesions in treatment group vs. placebo and significant slowing of disease progression (increase in remission). However, there were fatal cases of progressive multifocal leukoencephalopathy due to loss of immune surveillance. This trial dues illustrate the heavy involvement of the immune system.
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