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

Abstract

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.

Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors

“…The hydrophobic CHC derivatives 82 , while being effective fibrillation inhibitors, are reportedly less efficient in preventing oligomerization. On the other hand, CTR fragments 83 , 84 are more successful in mediating both oligomerization and fibrillogenesis through diverse mechanisms. Recent experiments establish the amyloid inhibition properties of the NTR Aβ fragment that is mainly hydrophilic in nature.…”

Modulation of aggregation with an electric field; scientific roadmap for a potential non-invasive therapy against tauopathies

“…1 Although this number is expected to increase to 132 million by 2050, there is no clinically approved therapy to cure or retard its progression. 1 Promising therapeutic strategies under research include native state stabilisation or brillation inhibition using small molecules, 2-6 immunotherapy, 7,8 peptide or peptidomimetics, [9][10][11][12][13][14][15][16][17][18] nanoparticles, 19,20 transient metals, [21][22][23][24] supramolecular inhibition of brillation 25,26 and sequestering the monomeric form of the peptide. 27 Nucleation-dependent aggregation is one of the most accepted models for the formation of amyloid brils.…”

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

“…The first class is peptide based inhibitors, which are derived from different regions of the amyloidogenic peptide sequence. The homologous fragment could bind to a complementary sequence in the full-length protein, which results in interfering with subsequent protein self-assembly and favoring to disassemble preformed fibrils (33,34). Some drawbacks have limited the clinical use of β-sheet breaker peptides, such as the cost of preparation, hydrosolubility, and oral bioavailability.…”