Modulation of Amyloid β-Protein (Aβ) Assembly by Homologous C-Terminal Fragments as a Strategy for Inhibiting Aβ Toxicity.
Self-assembly of amyloid β-protein (Aβ) 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 Aβ based on the assumption that such peptides would bind to full-length Aβ, 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-β structure of Aβ amyloid fibrils using β-sheet-breaker peptides derived from the central hydrophobic cluster of Aβ. Though this approach is effective in inhibiting fibril formation, it is generally inefficient in preventing Aβ oligomerization. An alternative approach is to use peptides derived from the C-terminus of Aβ, 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 β-sheet formation. Here, we review the strategy of using C-terminal fragments of Aβ as modulators of Aβ assembly and discuss the relevant challenges, therapeutic potential, and mechanisms of action of such fragments.
West Virginia University , Morgantown, West Virginia 26506, United States.
Huiyuan
H
Li
Biomedical Science and Biochemistry, Research School of Biology, The Australian National University , Acton, ACT 2601, Australia.
Farid
F
Rahimi
Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles , Neuroscience Research Building 1, Room 451 635 Charles E. Young Drive South, Los Angeles, California 90095-7334, United States.
Gal
G
Bitan
D000494:Allosteric Regulation / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments
Alzheimer’s disease; aggregation; amyloid; oligomerization; peptide; toxicity