Axonal regeneration, but not myelination, is partially dependent on local cholesterol reutilization in regenerating nerve

A recycling pathway in peripheral nerve permits cholesterol from degenerati ng myelin to be salvaged by macrophages and resupplied to myelinating Schwa nn cells by locally produced lipoproteins. A similar reutilization of chole sterol by regenerating axons has been proposed but not demonstrated. Neurit es in culture, however, do take up cholesterol and cholesterol-containing L ipoproteins, where these molecules are found to promote neurite extension. To test the requirement for cholesterol reutilization in axon regeneration and myelination, we examined 2 models of blocked intracellular cholesterol transport: 1) bone marrow transplants from Niemann-Pick C mice into wild-ty pe recipient mice, and 2) imipramine treatment. Following nerve crush in th ese models, we found that unusually large, debris-filled macrophages appear ed and persisted for many weeks. A morphometric analysis of regenerating ne rves revealed that myelination proceeded at a normal rate (normal g-ratios) , but that axon growth was retarded (decreased fiber numbers and diameters) in these animals. Cholesterol synthesis was elevated in these nerves, indi cating that Schwann cells compensated for the decreased exogenous supply of cholesterol by up-regulating de novo synthesis to support myelination. The se data indicate that Schwann cells are not dependent on cholesterol reutil ization to support myelination, but that optimal axonal regeneration is dep endent on a local supply of cholesterol.