The physiological function of BACE1 - is BACE1 a safe therapeutic target?

Coordinator:    Prof. Dr. Christian Haass;Dr. Alistair N. Garratt
Institution: Ludwig-Maximilians-Universität, München
The Amyloid-beta (Aβ) Peptide plays an essential role in the pathology of Alzheimer disease. It is produced through processing of the Amyloid-Precursor-Protein (APP) via two molecular scissors, so-called proteases, the β- and γ-secretases. Inhibition of these secretases is one of the most promising therapeutic approaches for treatment of Alzheimer disease. Possible side-effects have to be brought into consideration, however, due to the physiological functions of the proteases. As the physiological functions of the β-secretase, BACE1 were at first unclear, we saw it as necessary to investigate the functions of BACE1 through genetics and pharmacologic treatment in mice, both in developing and adult animals, in order to assess possible side-effects that could result from treatment with BACE1 inhibitors. We first showed that BACE1 is essential for the myelination (electrical insulation) of peripheral nerves via processing and activation of an isoform (type III) of the Neuregulin-1 (Nrg1) protein made by the nerve cells. Type III Nrg1 functions as a signaling molecule and stimulates the production of myelin sheaths by the accompanying Schwann cells, which ensheath the nerve cell processes (axons) ( In addition, we discovered that BACE1 cuts type III Nrg1 twice, thereby releasing the active part of the molecule, which triggers the Schwann cells to produce myelin ( Nrg1 is important not only for the myelination of the peripheral nervous system, but also for the development and maintenance of muscle spindles, which send important information to the brain about the stretch and position of muscles. In a collaboration with the group of Prof. Carmen Birchmeier (MDC, Berlin) we found that the BACE1-dependent processing of other Nrg1 isoforms (principally Type I Nrg1) plays a key role for coordination of movements ( It can be expected from these results that inhibition of BACE1 in patients could lead to a loss of muscle spindles and therefore to problems with motor coordination. Our work is therefore important to the development of drugs against Alzheimer disease that will have fewer harmful side-effects.

Fig. 1: BACE1 cleaves and activates different Nrg1 isoforms to stimulate myelination of peripheral nerves and muscle spindle formation/maintenance
Type III Nrg1 (red arrows) and Type I Nrg1 (blue arrows) are cleaved by BACE1 (orange scissors). Activated Type III Nrg1 stimulates Schwann cells (yellow ovals) to produce myelin insulation whilst Type I Nrg1 triggers development and maintenance of the muscle spindle. Nrg1 signaling occurs via the ErbB2/ErbB3 receptors (black/green bars) expressed in Schwann cells and the muscle spindle. Understanding the physiological functions of BACE1/Nrg1 signaling is essential for the development of safer drugs for the treatment of Alzheimer disease.

Fig. 2: Neuregulin-1 isoforms are cleaved and activated by BACE1
Neuregulin-1 (Nrg1) is a cell surface protein that exists in different isoforms, shown schematically, and that contain sites (red arrows) that are cleaved by BACE1. Both Nrg1 and BACE1 are expressed throughout the nervous system. Cleavage by BACE1 results in release of Types I and IV Nrg1 away from the cell surface (horizontal shaded bar), for example around the muscle spindle. Type III Nrg1 remains initially anchored at the axonal surface via an N-terminal hydrophobic segment (Hy) within the cysteine-rich domain (CRD), and a second BACE1 cleavage results in the release of the EGF domain, which can stimulate cells in the vicinity (e.g. Schwann cells). Abbreviations: Ig, immunoglobulin; glyco, glycosylated; EGF, epidermal growth factor-like; Hy, hydrophobic; CRD, cysteine-rich domain.
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