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BACE1 in central nervous system myelination revisited

Molecular Psychiatry volume 17, pages 237–239 (2012)Cite this article

The inhibition of the β-secretase enzyme, BACE1, has emerged as a prime therapeutic target for Alzheimer's disease, due to its central role in the processing of the amyloid precursor protein into the pathogenic 42 amino acid form of Aβ.1 As Bace1 −/− mice are viable and fertile, it was previously thought that the therapeutic inhibition of BACE1 will produce few adverse effects.2, 3 However, recent reports have provided evidence that Bace1−/− mice display severe hypomyelination of central and peripheral nervous system axons by impaired processing of neuregulin 1 type III, an EGF-like growth factor.4, 5 Although the role of neuregulin 1 in the myelination of the peripheral nervous system by Schwann cells is firmly established,6 a recent study has provided compelling evidence that oligodendrocytes do not require neuregulin 1/ErbB signaling to generate myelin in the central nervous system (CNS).7 In light of these new findings, we revisited the role of BACE1 in the CNS by analyzing the formation of myelin in the corpus callosum of Bace1−/− mice. Furthermore, we investigated the role of BACE1 in remyelination by using the demyelinating toxin cuprizone.

Using electron microscopy we evaluated the myelin thickness of 150–160 axons per animal (n=45 animals) by calculating the g-ratios (axon diameter/fiber diameter). First, we compared the animals in the untreated groups that had not received cuprizone. The myelin sheath thickness of untreated animals did not differ significantly between Bace1−/− mice and wild-type littermates (0.670±0.023 for wild-type vs 0.681±0.023 for knock-out, P=0.314 as determined by two-way analysis of variance, Figure 1c). In addition, myelin in the corpus callosum of Bace1−/− mice exhibited an intact ultrastructure and there were no differences in axonal size distribution of myelinated fibers (Figure 1b and e). Strikingly, when the cuprizone-treated animals were examined, a small, but significant difference in myelin sheath thickness was observed between Bace1−/− mice and the wild-type littermates (0.716±0.019 vs 0.748±0.030, P=0.003, Figure 1c). To determine the possible effects on axon size, we sorted the myelinated axons by caliber. Treatment with cuprizone resulted in an axonal size shift of the myelinated fibers. There was a smaller number of thin and a higher number of thick axons in the treatment groups as compared with the untreated mice. Yet, no differences between the two genotypes were observed (Figure 1e). Comparable results were obtained when the data of the g-ratio/axon caliber relation was generated as scatter plots: treated animals have slightly thinner myelin sheaths and bigger axons as compared with the control group (Figure 1d).

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Authors and Affiliations

  1. Max Planck Institute of Experimental Medicine, Göttingen, Germany

    H Treiber & M Simons

  2. Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    N Hagemeyer & H Ehrenreich

  3. Department of Neurology, University of Göttingen, Göttingen, Germany

    M Simons

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  1. H Treiber
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  2. N Hagemeyer
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  3. H Ehrenreich
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  4. M Simons
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Correspondence to M Simons.

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Treiber, H., Hagemeyer, N., Ehrenreich, H. et al. BACE1 in central nervous system myelination revisited. Mol Psychiatry 17, 237–239 (2012). https://doi.org/10.1038/mp.2011.140

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