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Bace1 modulates myelination in the central and peripheral nervous system

Nature Neuroscience volume 9, pages 1520–1525 (2006)Cite this article

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.

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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.

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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).

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Authors and Affiliations

  1. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Xiangyou Hu, Caitlin W Hicks, Wanxia He, Wendy B Macklin, Bruce D Trapp & Riqiang Yan

  2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Philip Wong

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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.

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Correspondence to Riqiang Yan.

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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)

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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

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