Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, Nave KA, Saftig P, Haass C, Garratt AN, Bennett DL, Birchmeier C. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 2013 Jun 21; PubMed.
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University of British Columbia
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:
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, Destrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5. Epub 2006 Nov 12 PubMed.
German Center for Neurodegenerative Diseases (DZNE)
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.
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