Can injured nerves in mice rebuild their myelin without the LDL cholesterol receptor?

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After peripheral nerve injury, cholesterol from degenerating myelin is retained locally inside macrophages. Schwann cells subsequently reuse it to make new myelin during nerve regeneration.

Substantial evidence indicates that this cholesterol conservation and reuse occurs through lipoprotein-mediated transport between cells, but the identities of the lipoproteins and their receptors remain unresolved. Because Schwann cells in regenerating nerves have been reported to express the low-density lipoprotein (LDL) receptor, or LDLR, the researchers used LDLR knockout mice to test this receptor’s potential role in cholesterol reuse.

In this experimental comparison, the researchers crushed the sciatic nerves of LDLR knockout and wild-type mice and examined them 3 days to 10 weeks later. Morphometric analyses and measurements of mRNA levels for myelin protein P(0) indicated that axon regeneration and myelination proceeded normally in the LDLR knockout mice.

The researchers then measured hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and mRNA levels to determine whether Schwann cells compensated for the missing LDLR by increasing cholesterol synthesis. Unexpectedly, these measures remained at the same downregulated levels seen in regenerating nerves of wild-type mice.

The apparently normal nerve regeneration, together with the absence of compensatory upregulation of cholesterol synthesis in LDLR knockout mice, indicates that other lipoprotein receptors must be primarily responsible for cholesterol uptake by Schwann cells.