Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bace1 modulates myelination in the central and peripheral nervous system

Abstract

Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the β-secretase site. Apart from this cleavage, the functional importance of Bace1 in other physiological events is unknown. We show here that Bace1 regulates the process of myelination and myelin sheath thickness in the central and peripheral nerves. In Bace1-null mice, the process of myelination was delayed and myelin thickness was markedly reduced, indicating that genetic deletion of Bace1 causes hypomyelination. Bace1-null mice also showed altered neurological behaviors such as elevated pain sensitivity and reduced grip strength. Further mechanistic studies showed an altered neuregulin-Akt signaling pathway in Bace1-null mice. Full-length neuregulin-1 was increased and its cleavage product was decreased in the CNS of Bace1-null mice. Furthermore, phosphorylated Akt was also reduced. Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hypomyelination of hippocampal and optical nerves in Bace1-null mice.
Figure 2: Hypomyelination of sciatic nerves in Bace1-null mice.
Figure 3: Reduction of MBP and PLP in Bace1-null brains.
Figure 4: Altered pain sensitivity in Bace1-null mice.
Figure 5: Increased full-length neuregulin-1 and reduced Akt phosphorylation in Bace1-null mice.

Similar content being viewed by others

References

  1. Vassar, R. et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    Article  CAS  Google Scholar 

  2. Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533–537 (1999).

    Article  CAS  Google Scholar 

  3. Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. 14, 419–427 (1999).

    Article  CAS  Google Scholar 

  4. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).

    Article  CAS  Google Scholar 

  5. Sisodia, S.S. & George-Hyslop, P.H. γ-Secretase, Notch, Aβ and Alzheimer's disease: where do the presenilins fit in? Nat. Rev. Neurosci. 3, 281–290 (2002).

    Article  CAS  Google Scholar 

  6. Tanzi, R.E. & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545–555 (2005).

    Article  CAS  Google Scholar 

  7. Cai, H. et al. BACE1 is the major beta-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 4, 233–234 (2001).

    Article  CAS  Google Scholar 

  8. Luo, Y. et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished beta-amyloid generation. Nat. Neurosci. 4, 231–232 (2001).

    Article  CAS  Google Scholar 

  9. Roberds, S.L. et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 10, 1317–1324 (2001).

    Article  CAS  Google Scholar 

  10. Yan, R., Han, P., Miao, H., Greengard, P. & Xu, H. The transmembrane domain of the Alzheimer's β-secretase (BACE1) determines its late Golgi localization and access to β-amyloid precursor protein (APP) substrate. J. Biol. Chem. 276, 36788–36796 (2001).

    Article  CAS  Google Scholar 

  11. Walter, J. et al. Phosphorylation regulates intracellular trafficking of β-secretase. J. Biol. Chem. 276, 14634–14641 (2001).

    Article  CAS  Google Scholar 

  12. Kitazume, S. et al. Alzheimer's β-secretase, β-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc. Natl. Acad. Sci. USA 98, 13554–13559 (2001).

    Article  CAS  Google Scholar 

  13. Lichtenthaler, S.F. et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J. Biol. Chem. 278, 48713–48719 (2003).

    Article  CAS  Google Scholar 

  14. Li, Q. & Sudhof, T.C. Cleavage of amyloid-β precursor protein and amyloid-β precursor-like protein by BACE 1. J. Biol. Chem. 279, 10542–10550 (2004).

    Article  CAS  Google Scholar 

  15. Pastorino, L. et al. BACE (β-secretase) modulates the processing of APLP2 in vivo. Mol. Cell. Neurosci. 25, 642–649 (2004).

    Article  CAS  Google Scholar 

  16. von Arnim, C.A. et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J. Biol. Chem. 280, 17777–17785 (2005).

    Article  CAS  Google Scholar 

  17. Wong, H.K. et al. β subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J. Biol. Chem. 280, 23009–23017 (2005).

    Article  CAS  Google Scholar 

  18. Kim, D.Y., Ingano, L.A., Carey, B.W., Pettingell, W.H. & Kovacs, D.M. Presenilin/γ-secretase-mediated cleavage of the voltage-gated sodium channel β2-subunit regulates cell adhesion and migration. J. Biol. Chem. 280, 23251–23261 (2005).

    Article  CAS  Google Scholar 

  19. Laird, F.M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693–11709 (2005).

    Article  CAS  Google Scholar 

  20. Dominguez, D. et al. Phenotypical and biochemical analysis of BACE1 and BACE2 deficient mice. J. Biol. Chem. 280, 30797–30806 (2005).

    Article  CAS  Google Scholar 

  21. He, W. et al. Reticulon family members modulate BACE1 activity and amyloid-β peptide generation. Nat. Med. 10, 959–965 (2004).

    Article  CAS  Google Scholar 

  22. Kamal, A., Almenar-Queralt, A., LeBlanc, J.F., Roberts, E.A. & Goldstein, L.S. Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP. Nature 414, 643–648 (2001).

    Article  CAS  Google Scholar 

  23. Lemke, G. Neuregulin-1 and myelination. Sci. STKE published online 7 March 2006 (doi:10.1126/stke.3252006pe11).

  24. Woolf, C.J. No Nogo: now where to go? Neuron 38, 153–156 (2003).

    Article  CAS  Google Scholar 

  25. Sherman, D.L. & Brophy, P.J. Mechanisms of axon ensheathment and myelin growth. Nat. Rev. Neurosci. 6, 683–690 (2005).

    Article  CAS  Google Scholar 

  26. Michailov, G.V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

    Article  CAS  Google Scholar 

  27. Cellerino, A., Carroll, P., Thoenen, H. & Barde, Y.A. Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Mol. Cell. Neurosci. 9, 397–408 (1997).

    Article  CAS  Google Scholar 

  28. Chen, S. et al. Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function. J. Neurosci. 26, 3079–3086 (2006).

    Article  CAS  Google Scholar 

  29. Gillespie, C.S. et al. Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 26, 523–531 (2000).

    Article  CAS  Google Scholar 

  30. Wrabetz, L. et al. P0 glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J. Cell Biol. 148, 1021–1034 (2000).

    Article  CAS  Google Scholar 

  31. Yin, X. et al. Evolution of a neuroprotective function of central nervous system myelin. J. Cell Biol. 172, 469–478 (2006).

    Article  CAS  Google Scholar 

  32. Ogata, T. et al. Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J. Neurosci. 24, 6724–6732 (2004).

    Article  CAS  Google Scholar 

  33. Taveggia, C. et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).

    Article  CAS  Google Scholar 

  34. Calaora, V. et al. Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro. J. Neurosci. 21, 4740–4751 (2001).

    Article  CAS  Google Scholar 

  35. Sussman, C.R., Vartanian, T. & Miller, R.H. The ErbB4 neuregulin receptor mediates suppression of oligodendrocyte maturation. J. Neurosci. 25, 5757–5762 (2005).

    Article  CAS  Google Scholar 

  36. Ozaki, M., Itoh, K., Miyakawa, Y., Kishida, H. & Hashikawa, T. Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner. J. Neurochem. 91, 176–188 (2004).

    Article  CAS  Google Scholar 

  37. Carteron, C., Ferrer-Montiel, A. & Cabedo, H. Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival. J. Cell Sci. 119, 898–909 (2006).

    Article  CAS  Google Scholar 

  38. Bao, J., Wolpowitz, D., Role, L.W. & Talmage, D.A. Back signaling by the Nrg-1 intracellular domain. J. Cell Biol. 161, 1133–1141 (2003).

    Article  CAS  Google Scholar 

  39. Liu, X. et al. Release of the neuregulin functional polypeptide requires its cytoplasmic tail. J. Biol. Chem. 273, 34335–34340 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank M. Yin (electron microscopy facility at Cleveland Clinic Lerner Research Institute) for her assistance in electron microscopic analysis, S. Naravanan for the discussion of electron microscopic experiments and G. Kidds for his assistance in confocal imaging. We would also like to thank B. Lamb, Q. Shi, X. Zhou and J. Yang for discussion during this study. Antibody to PLP was a gift of S. Pfeiffer (University of Connecticut, Farmington, Connecticut, USA) and antibody to MOG was a gift from M. Gardinier (University of Iowa, Iowa City, Iowa, USA). This study was supported by the Cleveland Clinic and grants from the US National Institutes of Health to R.Y. (AG025493), B.D.T. (NS029818), W.B.M. (NS25304) and P.W. (NS41438).

Author information

Authors and Affiliations

Authors

Contributions

X.H., C.W.H. and W.H. performed experiments, analyzed data, prepared figures and contributed to the preparation of the manuscript. P.W. provided Bace1-null mice. W.B.M. and B.D.T. contributed to the data analysis and the preparation of the manuscript. R.Y. supervised the experiments, analysis of data and preparation of the manuscript.

Corresponding author

Correspondence to Riqiang Yan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Reduced myelination in BACE1–null central nervous system. (PDF 4232 kb)

Supplementary Fig. 2

MBP is reduced in the cortex and hippocampus of BACE1–null mice. (PDF 845 kb)

Supplementary Fig. 3

Validation of abolished processing of APP in BACE1–null mice. (PDF 292 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, X., Hicks, C., He, W. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9, 1520–1525 (2006). https://doi.org/10.1038/nn1797

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1797

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing