Key residue for aggregation of amyloid-β peptides

Abstract

Amyloid-b peptides (Abs) are associated with Alzheimer’s disease and have two isoforms: Ab40 and Ab42. Although the difference between Ab40 and Ab42 is only two additional C-terminal residues, Ab42 aggregates much faster and is more toxic than Ab40. It is unknown what role the C-terminal two residues play in accelerating aggregation. Clarifying the differences between the oligomerization processes of Ab40 and Ab42 is essential to elucidate the key factors of oligomerization. Performing Hamiltonian replica-permutation molecular dynamics simulations for Ab40 and Ab42 to investigate the early oligomerization process, we identified the key residue, Arg5, for the Ab42 dimerization. The two additional residues in Ab42 allow the C-terminus to form contact with Arg5, and this contact stabilizes the b-hairpin. This b-hairpin promotes the intermolecular b-bridge formation. We also conducted experiments on Ab aggregations to validate these simulation results and confirmed that mutations of Arg5 remarkably suppressed the Ab42 aggregation.

Aβ–ganglioside interactions in the pathogenesis of Alzheimer's disease

“…The His 14 -Val 21 and Ile 31 -Val 36 segments form helical structures in lyso-GM1 micelles (helicity 53%) [81] and the sugar-lipid interface is primarily perturbed [82]. A recent study, however, indicated that the former helix is destabilized in GM1 micelles and a monomeric hairpin structure is also formed by a helix-to-β-sheet transition [83]. At a Aβ-to-GM1 ratio of 0.067, the two C-terminal residues exhibit two distinct conformational states that are reactive with the amyloid-specific dye thioflavin T [84].…”

Metastable Alpha-rich and Beta-rich Conformations of Small Aβ42 Peptide Oligomers

“…Beta-rich Aβ42 oligomers ranging from elongated to compact shapes were described by ss-NMR spectroscopy, ion mobility separation coupled to mass spectrometry, and simulations, featuring multiple interfaces, mixed parallel/antiparallel strands, perpendicular β-sheets and β-barrels. 6,7,11,28,[45][46][47][48][49] For instance, atomistic simulations in explicit solvent revealed β-barrel motifs in Aβ42 trimer and tetramer. 48,50,51 An hexamer peptide barrel was found experimentally to be the building block of Aβ protofibrils.…”

Amyloid, a Jekyll and Hyde Molecule Inducing Neuronal Decline and Cognitive Dysfunction is Also a Unique Molecular Template used in Nano-electronics, Light Capture Photovoltaics, and Biosensors in Neuromorphic Computing.

“…Aβ40 and Aβ42 oligomers of amyloid-β (Aβ) peptide associated with AD only differ by two Cterminal residues, however Aβ42 aggregates much faster than Aβ40 and is more toxic, forming porelike structures in cell membranes [28][29][30]. The additional C-terminal residues in Aβ42 allow electrostatic interactions which stabilize the β-hairpin and promote dimer formation and oligomerization through intermolecular β-bridge formation [31,32]. A combination of hydrophobic and charged amino acids in Aβ peptides also contribute to aggregate formation; glycosaminoglycans (GAGs) also act at the earliest stage of fibril formation, namely during amyloid-beta nucleation [33].…”