Treatment strategies targeting amyloid β-protein

Abstract

With the advent of the key discovery in the mid-1980s that the amyloid β-protein (Aβ) is the core constituent of the amyloid plaque pathology found in Alzheimer disease (AD), an intensive effort has been underway to attempt to mitigate its role in the hope of treating the disease. This effort fully matured when it was clarified that the Aβ is a normal product of cleavage of the amyloid precursor protein, and well-defined proteases for this process were identified. Further therapeutic options have been developed around the concept of anti-Aβ aggregation inhibitors and the surprising finding that immunization with Aβ itself leads to reduction of pathology in animal models of the disease. Here we review the progress in this field toward the goal of targeting Aβ for treatment and prevention of AD and identify some of the major challenges for the future of this area of medicine.

Figure 1.

Amyloidogenic processing of amyloid precursor protein (APP) by BACE1 and γ-secretase. The figure depicts the principal proteolytic processing steps of APP leading to the production of 40–42-residue amyloid β (Aβ) peptide, the subsequent steps ultimately culminating in compaction and deposition of the peptide in β-amyloid plaques in brain of AD patients (and transgenic AD mouse models), and the primary point of intervention by the different therapeutic antiamyloid approaches discussed in this article.

Figure 2.

Electron micrograph based 3D structure of the γ-secretase complex. (A) Surface rendering of the 3D reconstruction. The first row displays side views generated by rotating the map around a vertical axis, and the second row shows tilted views by rotating around a horizontal axis. The rotation angles are shown within each view. Two openings at the top and bottom are labeled H1 and H2, respectively, where visible. The top density is labeled NCT because the lectin labeling showed that the NCT ectodomain is located at this surface. (B) The potential transmembrane segment with the belt-like structure is outlined in blue by two parallel dashed lines, 60 Å apart. For size comparison, a typical transmembrane α-helix, taken from the rhodopsin structure (Protein Data Bank ID code 1GZM), is shown to the left of the structure. (C) A cut-open view of the γ-secretase complex from the side, revealing a large central chamber and one opening (H1) at the top and one at the bottom (H2). Two weak-density lateral regions are labeled with asterisks. (Image is from Lazarov et al. 2006; printed with permission from D. Selkoe.)

Figure 3.

Crystal structure of BACE1 complexed with a small molecule inhibitor. The crystal structure of BACE1 complexed to inhibitor OM99-2. Stereo view of the polypeptide backbone of BACE1 is shown as a ribbon diagram. The amino-terminal and carboxy-terminal lobes are blue and yellow, respectively, insertion loops (relative to pepsin) designated A–G in the carboxy-terminal lobe are magenta, and the COOH-terminal extension unique to BACE is green. The inhibitor bound between the lobes is shown in red. (Modified from Hong et al. 2000.)

Figure 4.

Spatial energy flow diagram of protein folding. The diagram depicts how, following immediate synthesis, a polypeptide initially has a very high level of possible folding and conformational states (10¹⁰). The drive toward a lower energy state results in a reduced number, although still extremely high, of possible conformational states. Eventually with time, these various states, by different routes, converge toward a small number of possibilities, shown on the bottom of the figure. (Modified from Dinner et al. 2000.)

Figure 5.

Reduction of Aβ plaque pathology by Aβ immunotherapy in mouse APP transgenic mice and patients suffering from Alzheimer disease. The left panel in each image illustrates amyloid pathology in control (A), in reference (B), or at a baseline (C) and the right panel in each image illustrates amyloid pathology following immunotherapy. (A) Mice immunized with full-length Aβ peptide at mid-age (when plaques are already present) 6 months later show an actual reduction in plaque burden relative to vehicle-treated controls. (From Schenk et al. 1999; reprinted with permission from the author.) (B) Patients who were immunized with AN 1792 (full-length Aβ peptide) from a phase 1 study who eventually died and went to autopsy exhibited low levels of absence of Aβ plaques. (Modified from Nicoll et al. 2006; reprinted with permission from the author.) (C) Living patients from a phase 2 study treated with bapinuezumab (a humanized monoclonal antibody directed to the amino-terminal region of Aβ) showed a reduced level of PET-PIB (positron-emission tomography-Pittsburgh compound B) retention following treatment, suggesting reduced Aβ plaque burden. (From Rinne et al. 2010; reprinted with permission from the author.)