Scientists have discovered yet another function for β-secretase (BACE1), the enzyme that kick-starts amyloidogenic processing of the amyloid-β precursor protein. In the June 21 EMBO Journal, researchers led by Carmen Birchmeier, Max Delbrück Center for Molecular Medicine, Berlin, reported that mice require BACE1 to form and sustain muscle spindles. These bundles of nerve fibers sense changes in the length of the muscle and convey sensory information to the central nervous system. Without the secretase, motor coordination falters. Some of the paper's main findings were presented at a recent meeting at the Gladstone Institute of Neurological Disease in San Francisco (see ARF conference story). Scientists are intensely scrutinizing BACE1 as a target for ameliorating Alzheimer's disease pathology, but the research and development of BACE inhibitors has proven challenging. In mid-June, Eli Lilly halted the Phase 2 trial of its BACE1 inhibitor due to liver toxicity (ARF news story).

In addition to processing APP, BACE1 plays an important role in the developing nervous system. Peripheral nerves in newborn BACE1 knockout mice are thinly myelinated (Willem et al., 2006; Hu et al., 2006). However, the new study shows the spindle phenotype not only during development but also when BACE1 is knocked-out or inhibited in adulthood.

First author Cyril Cheret and colleagues show that BACE1 deficiency in adult mice impairs motor coordination. The movement defects stem from abnormal morphology and low numbers of muscle spindles. Similar defects appeared in wild-type mice treated with the BACE1 inhibitor LY2811376, a Lilly compound that reduced Aβ in cerebrospinal fluid of healthy volunteers. Lilly halted development of this compound because of toxic effects in rats (May et al., 2011).

The current study also showed that spindle formation and maturation relies on BACE1 processing of neuregulin 1 (Nrg1), a transmembrane protein that controls myelination. Recently, co-author Christian Haass at Ludwig-Maximilians University, Munich, reported that BACE1 and another protease, the disintegrin and metalloproteinase ADAM10, cleave neuregulin 1 to release a fragment that signals in paracrine fashion and rescues myelination in BACE1 knockout zebrafish (Fleck et al., 2013; van Bebber et al., 2013). The present work confirms, in mice, that BACE1 deficiency leads to reduced neuregulin 1 signaling.

“This is a scientifically exciting story that is genetically well-controlled,” noted Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich (see full comment below).

In addition to its basic science contribution, the work has ramifications for BACE1 inhibitors under development for AD. In light of recent studies that uncovered additional BACE1 substrates (see ARF news story), the present research suggests that “we have to be cautious when modulating or inhibiting BACE1 to treat AD phenotypes,” Weihong Song of the University of British Columbia, Vancouver, Canada, wrote in an email to Alzforum (see full comment below). Lichtenthaler noted that ongoing clinical trials are likely to answer the open question of whether phenotypes seen in mouse will appear in people, (see ARF conference story).—Esther Landhuis

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Comments on News and Primary Papers

  1. Previously, Christian Haass’s group (Willem et al., 2006) and Riqiang Yan’s team (Hu et al., 2006) demonstrated that BACE1 regulates myelination by processing type III NRG1, and that disruption of the BACE1 gene resulted in hypomyelination in the central and peripheral nervous system. In the present EMBO Journal report, they confirmed that NRG1 I is processed by BACE1 and that BACE1 deficiency reduced NRG1 signaling. Furthermore, they showed that BACE1-NRG1 plays an important role in the formation and maturation of the muscle spindle. Such effects impaired movement coordination in adult mice.

    The novel finding here is that the BACE1-NRG1 pathway not only affects myelination as previously reported, it now has a new biological function and suggests inhibition of BACE1 could have a negative biological consequence. Presenilin is embryonic lethal when knocked out and causes major side effects when blocked in adult animals by γ-secretase inhibitors, which affect many important presenilin substrates, such as Notch. Unlike presenilin, BACE1-ko mice develop relatively normally. Inhibition of BACE1 has been shown as a very good target for AD drug development. However, recent studies revealed that BACE1 also has many substrates essential for many important biological events.

    We have to be cautious when we work on modulating/inhibiting BACE1 for treating AD phenotypes. BACE1 modulators that reduce APP processing to generate Aβ without significantly affecting NRG1 and other substrates would be good for AD drug development.

    References:

    . Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.

    . Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5. Epub 2006 Nov 12 PubMed.

    View all comments by Weihong Song
  2. This is a scientifically exciting story that is genetically well controlled, including the conditional knockout of the substrate neuregulin 1. The paper adds muscle spindle formation to the growing list of BACE1 in-vivo functions. Another important aspect is that the phenotype only shows up during development and when BACE1 is knocked out or inhibited in adulthood.

    The paper is an excellent contribution to basic science, but obviously has an impact on BACE1 inhibitors under development for AD. Whether the phenotypes observed in the mouse line (knockout or treated with inhibitor) also show up in patients remains to be seen and needs to be tested. However, we need to keep in mind that processes that are strongly affected in mice may not be affected to the same extent in man and vice versa. The ongoing clinical trials are likely to give us an answer to this question.

    View all comments by Stefan Lichtenthaler

References

News Citations

  1. Paracrine Signal From BACE1-Clipped Neuregulin Rescues Myelin
  2. Lilly Halts Phase 2 Trial of BACE Inhibitor Due to Liver Toxicity
  3. BACE Secrets: Newly Identified Substrates May Regulate Plasticity
  4. BACE Inhibitors Barrel Forward—Next Hurdles: Safety, Efficacy

Paper Citations

  1. . Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
  2. . Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5. Epub 2006 Nov 12 PubMed.
  3. . Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16. PubMed.
  4. . Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci. 2013 May 1;33(18):7856-69. PubMed.
  5. . Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. J Neurochem. 2013 Feb 14; PubMed.

Further Reading

Papers

  1. . Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci. 2013 May 1;33(18):7856-69. PubMed.
  2. . Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
  3. . Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. J Neurochem. 2013 Feb 14; PubMed.

Primary Papers

  1. . Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 2013 Jun 21; PubMed.