Peripheral nerve regeneration and cholesterol reutilization are normal in the low-density lipoprotein receptor...

Following peripheral nerve injury, cholesterol from degenerating myelin is retained locally within macrophages and subsequently reutilized by Schwann cells for synthesis of new myelin during nerve regeneration. Substantial evidence indicates this conservation and reutilization of cholesterol is accomplished via lipoprotein-mediated intercellular transport, although the identities of the lipoproteins and their receptors are unresolved. Because Schwann cells in regenerating nerve are reported to express the low-density lipoprotein (LDL) receptor (LDLR), we used the LDLR knockout mouse to examine the potential role of this receptor in cholesterol reutilization. Sciatic nerves were crushed in knockout and wild-type mice and examined 3 days to 10 weeks later. Morphometric analyses and measures of mRNA levels for myelin protein P(0), indicate that axon regeneration and myelination proceed normally in the LDLR knockout mouse. We therefore measured hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and mRNA levels to determine whether Schwann cells compensated for the absence of the LDLR by upregulating cholesterol synthesis. Unexpectedly, these measures remained at the same downregulated levels found in regenerating nerves of wild-type animals. The apparently normal nerve regeneration, coupled with the lack of any compensatory upregulation of cholesterol synthesis in the LDLR knockout mice, indicates that other lipoprotein receptors must be primarily involved in cholesterol uptake by Schwann cells.