3 July 2013. 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
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. 21 June 2013. Abstract