Targeting the β secretase BACE1 for Alzheimer's disease therapy

Abstract

The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer's disease, and will soon be tested in individuals with presymptomatic Alzheimer's disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer's disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer's disease.

Figure 1. APP processing and mutations affecting β-secretase cleavage

(A) APP is a type 1 membrane protein that is sequentially cleaved by two aspartic proteases to generate Aβ. First, the β-secretase enzyme cuts APP (1) to create the N-terminus of Aβ. Two APP fragments are produced: membrane-bound C99 and secreted sAPPβ ectodomain (grey). Second, C99 is cleaved by the γ-secretase enzyme (2) to generate the C-terminus of Aβ. Aβ (purple) is then released into the lumen of the endosome and secreted into the extracellular medium. An intracellular domain, C59 (black), is also produced. (B) The aminoacids in and around the Aβ domain of APP are represented as green circles. Aminoacids that affect β-secretase processing of APP in humans are shown in yellow circles, within which the wildtype residue is identified by the single-letter aminoacid code. The Lys670Asn/Met671Leu (Swedish) and Ala673Val mutations cause FAD by increasing the rate of β-secretase cleavage and Aβ production, whereas the Ala673Thr mutation protects against Alzheimer’s disease by doing the opposite. All three mutations occur at or within one aminoacid of the β-secretase cleavage site. Scissors show cleavage sites of the various secretases. APP=amyloid precursor protein. Aβ=amyloid β peptides. sAPPβ=soluble peptide APPβ. FAD=familial Alzheimer’s disease.

Figure 2. Primary structure and neuronal substrates of BACE1

(A) BACE1 is a 501 aminoacid type 1 transmembrane aspartic protease. The various subdomains of BACE1 are shown above the structure. Numbers refer to aminoacid positions. The two signature aspartic protease active site motifs at positions 93 and 289 are shaded orange. S–S denotes positions of disulphide bridges within the catalytic domain. N represents positions of N-linked glycosylation sites. R shows the positions of acetylated arginine residues. C marks the positions of S-palmitoylated cysteine residues. P shows the phosphorylation of serine 498. Ub denotes ubiquitination of lysine 501. (B) BACE1 substrates identified in primary cultured neurons are listed from those that are predominantly cleaved by BACE1 (BACE1 cleavage high; top) to those that are processed by BACE1 at a low level (bottom). These substrates also are cleaved by other proteases in the ADAM family, but the ADAM cleavage preference is opposite to that of BACE1. Adapted from Kuhn and colleagues, by permission of the European Molecular Biology Organization. ADAM=a disintegrin and metalloproteinase domain family.

Figure 3. BACE1 inhibitor LY2811376 bound within the active site of BACE1

In this x-ray cocrystal structure, LY2811376 is observed to hydrogen bond (dashed yellow lines) to both of the active site aspartic acid residues, here labelled ASP-32 and ASP-228, thus inhibiting the catalytic activity of the enzyme. Numbers represent lengths of hydrogen bonds in Angstroms. Other residues in the active site that interact with LY2811376 are shown in yellow. Adapted from May and colleagues, by permission of the Society for Neuroscience.