LONDON – Treating Alzheimer's disease (AD) by inhibiting a key enzyme that helps to generate amyloid-beta peptide sounded like a good strategy – but evidence is continuing to build, showing that the enzyme also has important other functions in the body.
The latest fly in the ointment is the discovery that the enzyme, Bace1, also controls the development of muscle spindles. The same study showed that mice that lack Bace1, or are treated with compounds that inhibit it, show movement abnormalities.
In AD, a protein found in the membranes of neurons called amyloid precursor protein (APP) is broken down to form amyloid-beta peptide. The latter accumulates in the brain, forming plaques.
The enzyme Bace1 (which stands for beta-site APP-cleaving enzyme) is needed in order to cleave the membrane-bound APP and release amyloid-beta peptide into the extracellular space. Scientists know that Bace1 is needed for that reaction, because knockout mice lacking functional copies of the gene encoding it make no amyloid-beta peptide.
Much research therefore has taken place into whether it would be possible to treat AD by inhibiting Bace1, with some candidate compounds reaching Phase II and Phase III trials.
In parallel, researchers have scrutinized the normal functions of Bace1 on the grounds that such a highly conserved enzyme must have roles other than that of causing the development of AD.
Scientists at the Max-Delbruck-Center for Molecular Medicine in Berlin, for example, have been probing Bace1 for many years. In 2006, a team led by Christian Haas found that Bace1 had an important role in nerve myelination. Other studies had shown that when the gene was knocked out in zebra fish, the fish had a movement abnormality. (See BioWorld International, Oct. 4, 2006.)
Now, the latest findings from the team suggested that inhibiting Bace1 could lead to unwanted side effects related to defective movement.
The study, published in the the June 21, 2013, issue of the EMBO Journal, showed that Bace1 is needed for the formation of muscle spindles – tiny sensory organs that are found throughout the muscles of vertebrates and which form at the point of contact between sensory nerves and muscle fibers. The role of the muscle spindles is to detect the degree of stretch of the muscle, and thus report information on the position of the limbs, for example, to the brain.
Carmen Birchmeier, professor at the Max-Delbruck-Center, said: "Our results show that mice that lack Bace1 proteins or are treated with inhibitors of the enzyme have difficulties in coordination and walking and also show reduced muscle strength. In addition, we were able to show that the combined activities of Bace1 and another protein, neuregulin-1, or Nrg-1, are needed to sustain the muscle spindles in mice and to maintain motor coordination."
Nrg-1 is a substrate of Bace1. It is known to help regulate the development and regeneration of the nervous system. That finding is in line with earlier work by other groups, which showed that genetic deletion of Nrg-1, or its receptor, from muscle tissue prevented the normal development of muscle spindles.
The title of the paper in the EMBO Journal is "Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles." The first author is Cyril Cheret, also from the Max-Delbruck-Center.
Cheret explained that some of the experiments involved reducing the signal strength of a specific form of neuregulin-1, called IgNrg1. During those experiments, he said, "increasingly severe defects in the formation and maturation of muscle spindles are observed in mice. Furthermore, it appears that Bace1 is required for full IgNrg1 activity. The graded loss of IgNrg1 activity results in the animals having increasing difficulties with movement and coordination."
Birchmeier concluded: "Our data indicate that one unwanted side effect of the long-term inhibition of Bace1 might be the disruption of muscle spindle formation and impairment of movement. This finding is relevant to scientists looking for ways to develop drugs that target the Bace1 protein and should be considered."
At least one company has decided to abandon development of a drug candidate compound for AD, which was said to block Bace1 activity. AC Immune SA, of Lausanne, Switzerland, began a Phase I/II trial in late 2008 of the small-molecule compound ACI-91.
The company announced in January that it was discontinuing development of ACI-91 because "Phase II results do not demonstrate efficacy of ACI-91 in patients with advanced Alzheimer's disease." (See BioWorld Today, Feb. 1, 2013.)