Myelin

Myelinated neurons have their axons segmentially covered with myelin, a spirally wrapped membrane (lamella). The myelin lamella is formed by glial cells that wrap the axon with protrusions, and then the inner leaflets of the plasma membrane fuse together, with no cytoplasm left. There can be up to 100 turns of myelin wrapped around an axon, and over half of the total diameter of the nerve fiber is made up of myelin lamellae. In CNS, interfascicular oligodendrocytes are the glial cells that form the myelin, each oligodendrocyte myelinating multiple axons and axon segments. In PNS, myelin is formed by glial Schwann cells, one myelin sheath per one Schwann cell. The length of myelin sheaths in PNS is ∼1 mm, with ∼1 µm gaps (nodes of Ranvier) between them, exposing the axon to the extracellular space. The voltage-gated Na+ channels are clustered at the nodes. Myelin between the nodes (internodes) allows the action potential to jump from one node to the next (saltatory conduction), increasing the signal transmission speed up to 200 fold. The nodes of Ranvier are also the sites of presynaptic specializations.

The composition of myelin is variable, especially between CNS and PNS. The water content of myelin is ∼40%. Most of the dry mass is made up of glycolipids, primarily galactocerebroside (galactosyl ceramide), and cholesterol and phospholipids. Myelin proteins consist mainly of proteolipid protein (PLP), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG).

Myelin contains also enzymes, including ones with steroid modifying and cholesterol esterifying activity. Phosphatidylcholine can possibly be synthesized within myelin. Carbonic anhydrase in myelin play a role in removing CO2 from axons.

Myelination is regulated by integrins. Oligodendrocytes express α6β1 integrin (laminin receptor), αvβ1, αvβ3, αvβ5, and αvβ8. Schwann cells express α6β1, α6β4, and α7β1 integrins.

Demyelination and remyelination

Genetic abnormalities that affect glial cells or signalling between axons and glial cells can cause defects in axon myelination. Inflammation and metabolic causes can lead to the loss of existing myelin sheaths. Schwann cells can resorpt myelin in peripheral demyelination. Demyelination diseases, such as multiple sclerosis (MS), can lead to various neurological symptoms. Demyelination may also be seen in the brains of subjects with TBI, AD, and some psychiatric disorders.

Following demyelination, the otherwise healthy axon can be remyelinated, leading to partial functional recovery. αv-subunit containing integrins in oligodendrocyte progenitor cells may have an important role in remyelination. The myelin sheaths generated during remyelination are typically thinner and shorter than the original.

Myelin contains considerable amounts of Ca2+, especially the myelin in spinal cord. Damage to the myelin may lead to the release of Ca2+, which may trigger necrotic cell death.

In the demyelinated axons, the number of Na+ channels are decreased, and voltage-gated K+ channels are increased and revealed from under the myelin sheaths. MS drug 4AP enhances conduction by blocking K+ channels.

PET imaging

Thioflavin-T and its derivatives have affinity toward the multiple β-sheet structures present in fibrillar amyloid-β deposits and MBP in myelin. PET tracer [11C]PIB is one of the thioflavin T derivatives, used extensively in imaging of amyloid plaques in neurological disorders, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, cerebral amyloid angiopathy (CAA), and traumatic brain injury (TBI). It has also been shown to be suitable for imaging myelin, and changes in myelin content, especially in multiple sclerosis (Stankoff et al., 2011; Veronese et al., 2015; Bodini et al., 2016). [11C]PIB uptake in cortex of late MS patients is not different from age-matched healthy subjects (Zeydan et al., 2017). Also some other amyloid PET tracers could be used in myelin imaging: for example [18F]florbetaben has decreased uptake in the white matter of MS patients (Matias-Guiu et al., 2015) and in pseudotumoral multiple sclerosis (Matias-Guiu et al., 2017).

Luxol fast blue is a copper phthalocyanine dye that has been used to stain myelin under light microscopy. The suitability of related compounds for myelin PET imaging has been studied, and led to development of promising stilbene derivatives (Wu et al., 2008). [11C]MeDAS has been found to be a sensitive and specific radiotracer for imaging of myelination in white matter (Wu et al., 2010) and in spinal cord (Wu et al., 2013).

MS drug 4AP binds to the K+-channels which are revealed from under the myelin sheaths after demyelination. The 18F-labelled drug derivative, [18F]3F4AP, is a promising tracer for detecting demyelinated brain regions (Burgarolas et al., 2018).


See also:



References:

Brady ST, Siegel GJ, Albers RW, Price DL (eds.): Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology, 8th ed. Academic Press, 2012. ISBN: 978-0-12-374947-5.

Lazzarini RA, Griffin JW, Lassman H, Nave K-A, Miller R, Trapp BD. Myelin Biology and Disorders. Elsevier Academic Press, 2004. ISBN: 978-0-12-439510-7.

Matthews PM, Datta G. Positron-emission tomography molecular imaging of glia and myelin in drug discovery for multiple sclerosis. Expert Opin Drug Discov. 2015; 10(5): 557-570. doi: 10.1517/17460441.2015.1032240.

Susuki K. Myelin: a specialized membrane for cell communication. Nature Education 2010; 3(9): 59.



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Created at: 2017-11-17
Updated at: 2018-01-16
Written by: Vesa Oikonen