Nerve Regeneration Occurs in the Absence of Apolipoprotein E in Mice
Corresponding Author
Brian Popko
Brain and Development Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Address correspondence and reprint requests to Dr. B. Popko at Brain and Development Research Center, CB 7250, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, U.S.A.Search for more papers by this authorJeffry F. Goodrum
Brain and Development Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorThomas W. Bouldin
Brain and Development Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorSunny H. Zhang
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorNobuyo Maeda
Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorCorresponding Author
Brian Popko
Brain and Development Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Address correspondence and reprint requests to Dr. B. Popko at Brain and Development Research Center, CB 7250, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, U.S.A.Search for more papers by this authorJeffry F. Goodrum
Brain and Development Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorThomas W. Bouldin
Brain and Development Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorSunny H. Zhang
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorNobuyo Maeda
Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Search for more papers by this authorAbstract
Abstract: The concentration of apolipoprotein E (apoE), a high-affinity ligand for the low-density lipoprotein receptor, increases dramatically in peripheral nerve following injury. This endoneurial apoE is thought to play an important role in the redistribution of lipids from the degenerating axonal and myelin membranes to the regenerating axons and myelin sheaths. The importance of apoE in nerve repair was examined using mutant mice that lack apoE. We show that at 2 and 4 weeks following sciatic nerve crush, regenerating nerves in apoE-deficient mice were morphologically similar to regenerating nerves in control animals, indicating that apoE is not essential for peripheral nerve repair. Moreover, cholesterol synthesis was reduced in regenerating nerves of apoE-deficient mice as much as in regenerating nerves of control animals. These results suggest that the intraneural conservation and reutilization of cholesterol following nerve injury do not require apoE.
Abbreviations
-
- apoE
-
- apolipoprotein E
-
- LDL
-
- low-density lipoprotein
-
- HMG-CoA
-
- 3-hydroxy-3-methylglutaryl-CoA
REFERENCES
- Beuche W. and Friede R. L. (1984) The role of non-resident cells in Wallerian degeneration. J. Neurocytol. 13, 767–796.
- Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., Hui D. Y., Mahley R. W., Gebicke-Haerter P. J., Ignatius M. J., and Shooter E. M. (1989) A role for apolipoprotein E, apolipoprotein A-1, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the sciatic nerve. J. Clin. Invest. 83, 1015–1031.
- Boyles J. K., Notterpek L. M., and Anderson L. J. (1990) Accumulation of apolipoproteins in the regenerating and remyelinating mammalian peripheral nerve. J. Biol. Chem. 265, 17805–17815.
- Brown M. C., Lunn E. R., and Perry V. H. (1992) Consequences of slow Wallerian degeneration for regenerating motor and sensory axons. J. Neurobiol. 23, 521–536.
- Day R., Gebhard R. L., Schwartz H. L., Strait K. A., Duane W. C., Stone B. G., and Oppenheimer J. H. (1989) Time course of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and messenger ribonucleic acid, biliary lipid secretion, and hepatic cholesterol content in methimazole-treated hypothyroid and hypophysectomized rats after triiodothyronine administration: possible linkage of cholesterol synthesis to biliary secretion. Endocrinology 125, 459–468.
- Fawcett J. W. and Keynes R. J. (1990) Peripheral nerve regeneration. Annu. Rev. Neurosci. 13, 43–60.
- Gelman B. B., Goodrum J. F., and Bouldin T. W. (1991) Macrophage apolipoprotein synthesis and endoneurial distribution as a response to segmental demyelination. J. Neuropathol. Exp. Neurol. 50, 383–407.
- Goldstein J. L., Basu S. K., and Brown M. S. (1983) Receptor mediated endocytosis of low-density lipoproteins in cultured cells. Methods Enzymol. 98, 241–260.
- Goodrum J. F. (1990) Cholesterol synthesis is down-regulated during regeneration of peripheral nerve. J. Neurochem. 54, 1709–1715.
- Goodrum J. F. (1991) Cholesterol from degenerating nerve myelin becomes associated with lipoproteins containing apolipoprotein E. J. Neurochem. 56, 2082–2086.
- Ignatius M. J., Gebicke-Haerter P. J., Skene J. H. P., Schilling K. H., Weisgraber K. H., Mahley R. W., and Shooter E. M. (1986) Expression of apolipoprotein E during nerve degeneration and regeneration. Proc. Natl. Acad. Sci. USA 83, 1125–1129.
- Ignatius M. J., Gebicke-Haerter P. J., Pitas R. E., and Shooter E. M. (1987a) Apolipoprotein E in nerve injury and repair. Prog. Brain Res. 71, 177–814.
- Ignatius M. J., Shooter E. M., Pitas R. E., and Mahley R. W. (1987b) Lipoprotein uptake by neuronal growth cones in vitro. Science 236, 959–962.
- Lemke G. and Axel R. (1985) Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40, 501–508.
- Mahley R. W. (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630.
- Müller H. W., Gebicke-Härter P. J., Hangen D. H., and Shooter E. M. (1985) A specific 37,000-dalton protein that accumulates in regenerating but not in non-regenerating mammalian nerves. Science 228, 499–501.
- Müller H. W., Ignatius M. J., Hangen D. H., and Shooter E. M. (1986) Expression of specific sheath cell proteins during peripheral nerve growth and regeneration in mammals. J. Cell Biol. 102, 393–402.
- Norton W. T. and Cammer W. (1984) Isolation and characterization of myelin, in Myelin P. Morell, ed, pp. 147–195. Plenum Press, New York .
- Perry V. H., Brown M. C., and Gordon S. (1987) The macrophage response to central and peripheral nerve injury. A possible role of macrophages in regeneration. J. Exp. Med. 165, 1218–1223.
- Piedrahita J. A., Zhang S. H., Hagaman J. R., Oliver P. M., and Maeda N. (1992) Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc. Natl. Acad. Sci. USA 89, 4471–4475.
- Rawlins F. A., Hedley-White E. T., Villegas G., and Uzman B. G. (1970) Reutilization of cholesterol-1,2-H in the regeneration of peripheral nerve. Lab. Invest. 22, 237–240.
- Rawlins F. A., Villegas G., Hedley-White E. T., and Uzman B. G. (1972) Fine structural localization of cholesterol-1,2-3H in degenerating and regenerating mouse sciatic nerve. J. Cell Biol. 52, 615–625.
- Rothe T. and Müller H. W. (1991) Uptake of endoneurial lipoprotein into Schwann cells and sensory neurons is mediated by low density lipoprotein receptors and stimulated after axonal injury. J. Neurochem. 57, 2016–2025.
- Skene J. H. P. and Shooter E. M. (1983) Denervated sheath cells secrete a new protein after nerve injury. Proc. Natl. Acad. Sci. USA 80, 4169–4173.
- Snipes G. J., McGuire C. B., Norden J. J., and Freeman J. A. (1986) Nerve injury stimulates the secretion of apolipoprotein E by non-neuronal cells. Proc. Natl. Acad. Sci. USA 83, 1130–1134.
- Spreyer P., Schaal H., Kuhn G., Rothe T., Unterbeck A., Olek K., and Müller H. W. (1990) Regeneration-associated high level expression of apolipoprotein D mRNA in endoneurial fibroblasts of peripheral nerve. EMBO J. 9, 2479–2484.
- Stahl N., Harry J., and Popko B. (1990) Quantitative analysis of myelin protein gene expression during development in the rat sciatic nerve. Mol. Brain Res. 8, 209–212.
- White F. V., Toews A. D., Goodrum J. F., Novicki D. L., Bouldin T. W., and Morell P. (1989) Lipid metabolism during early stages of Wallerian degeneration in the rat sciatic nerve. J. Neurochem. 52, 1085–1092.
- Williamson R., Lee D., Hagaman J., and Maeda N. (1992) Marked reduction of high density lipoprotein cholesterol in mice genetically modified to lack apolipoprotein A-1. Proc. Natl. Acad. Sci. USA 89, 7134–7138.
- Xin L., Richardson P. M., Gervais F., and Skamene E. (1990) A deficiency of axonal regeneration in C57BL/6J mice. Brain Res. 510, 144–146.
- Zhang S. H., Reddick R. L., Piedrahita J. A., and Maeda N. (1992) Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468–471.
