Damaging Cholesterol

D
I recently asked how can statins work in secondary progressive MS.

In the absense of any real insight, I came up with a few ideas one of which was involving the cholesterol pathway to control/induce nerve damage

Bezine M, Debbabi M, Nury T, Ben-Khalifa R, Samadi M, Cherkaoui-Malki M, Vejux A, Raas Q, de Sèze J, Moreau T, El-Ayeb M, Lizard G. Evidence of K+ homeostasis disruption in cellular dysfunction triggered by 7-ketocholesterol, 24S-hydroxycholesterol, and tetracosanoic acid (C24:0) in 158N murine oligodendrocytes. Chem Phys Lipids. 2017 pii: S0009-3084(17)30011-7

Imbalance in the homeostasis of K+ ions has been reported to contribute to the pathogenesis of neurodegenerative diseases. 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC), and tetracosanoic acid (C24:0), often found at increased levels in patients with Alzheimer’s disease and Multiple Sclerosis, are able to trigger numerous nerve cell dysfunctions.  We therefore studied the impact of 7KC, 24S-OHC, and C24:0 on 158N mouse oligodendrocytes, and determined their impact on K+ homeostasis. The effects of 7KC, 24S-OHC and C24:0 on lipid membrane organization and membrane potential were examined. 7KC, 24S-OHC and C24:0 induced changes in lipid content and the cytoplasmic membrane. These events were associated with increased [K+]i. The positive correlation between [K+]i and cell death supports the potential involvement of K+ in 7KC-, 24S-OHC-, and C24:0-induced cytotoxicity.

Cholesterol can be oxidised to become agents called oxysterols (see the diagram above). These can bind to cells including oligodendrocytes and they can block the action of a number of ion channels including some potasium channels and also potassium and sodium exhangers. These cause a rise in the concentration of potassium within the cell, which eventually trigger the entry of calcium and the suicide of the cell. This is a mechanism of inducing cell death in oligodendrocytes as shown here, but probablyother cell types as well

Statins will get rid of the cholesterol and in doing so will remove oxysterols and so this damaging mechanism will not occur. Perhaps getting rid of some of the potassium from inside the cell may be a route to countering this problem. I could suggest how this appraoch may be achieved but that’s another post.

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