Figure 2

Production of Aβ by proteolytic cleavage from APP followed by association of Aβ to form oligomers and fibrils, showing potential targets for anti-amyloid therapies. Aβ, the gray shaded box, is cleaved from APP by sequential action of 2 proteases; β-secretase carries out the initial cleavage to form the N-terminus of Aβ; γ-secretase then cleaves the C99 stub to produce the C-terminus of Aβ. The parallel dotted lines represent a membrane bilayer in which part of the C-terminal region of APP is anchored. Hence γ-secretase activity is a protease that cleaves a substrate within a membrane. Production of Aβ by secretase action leads to Aβ monomer, the concentration of which in the steady state is a balance between formation and degradation. Monomers can associate to form small oligomers that increase in size and eventually lead to fibril formation. One anti-amyloid strategy is to inhibit the enzymatic action of either secretase (shown by a black cross). A second strategy is to remove soluble and deposited Aβ using antibodies (shown as semicircles).