Peptide-Based Drug Design

72 Giannakis et al.
Fig. 1. Cleavage of APP via nontoxic and toxic pathways. Sequential cleavage of
APP by � and � secretases results in the production of the nonpathological fragment, P3
(A).Cleavageby� and � secretases results in the production of toxic A� fragments (B).
(From ref. 3.)
�-Secretase cleaves at position 17 of the A� domain (5). �-Secretase cleaves at
positions 1 and 11, which removes the large hydrophilic extracellular domain
of APP. �-Secretase, although not sequence specific, primarily cleaves at the
C-terminal end at positions 40 and 42, located within the hydrophobic transmembrane
domain of APP (6). Sequential cleavage by �/�-secretases results
in the generation of the nonpathogenic fragment called P3 (6). Cleavageby�and
�-secretases produces several variants of 39–43 residues, the most abundant
products being the A� peptide fragments 1-40 and 1-42, the latter of which is
particularly hydrophobic, resulting in a greater propensity to aggregate/fibrilize
and form plaques than the A� 1-40 isoform (7). The process of fibrilization
initially results in the formation of soluble oligomers, believed to consist mainly
of trimers and multiples of these oligomers, e.g., hexamers (8). These oligomers