Modulation of Amyloid β-Protein (Aβ) Assembly by Homologous C-Terminal Fragments as a Strategy for Inhibiting Aβ Toxicity

Self-assembly of amyloid beta-protein (A beta) into neurotoxic oligomers and fibrillar aggregates is a key process thought to be the proximal event leading to development of Alzheimer's disease (AD). Therefore, numerous attempts have been made to develop reagents that disrupt this process and prevent the formation of the toxic oligomers and aggregates. An attractive strategy for developing such reagents is to use peptides derived from A beta based on the assumption that such peptides would bind to full-length A beta, interfere with binding of additional full-length molecules, and thereby prevent formation of the toxic species. Guided by this rationale, most of the studies in the last two decades have focused on preventing formation of the core cross-beta structure of A beta amyloid fibrils using beta-sheet-breaker peptides derived from the central hydrophobic cluster of A beta. Though this approach is effective in inhibiting fibril formation, it is generally inefficient in preventing A beta oligomerization. An alternative approach is to use peptides derived from the C-terminus of A beta, which mediates both oligomerization and fibrillogenesis. This approach has been explored by several groups, including our own, and led to the discovery of several lead peptides with moderate to high inhibitory activity. Interestingly, the mechanisms of these inhibitory effects have been found to be diverse, and only in a small percentage of cases involved interference with beta-sheet formation. Here, we review the strategy of using C-terminal fragments of A beta as modulators of A beta assembly and discuss the relevant challenges, therapeutic potential, and mechanisms of action of such fragments.