Role of the carboxy groups of triterpenoids in their inhibition of the nucleation of amyloid β42 required for forming toxic oligomers

Abstract

Herein we report that a preferable inhibition of the nucleation phase of Aβ42, related to the formation of toxic oligomers, by triterpenoids from medicinal herbs originates from a salt bridge of their carboxy groups with Lys16 and 28 in Aβ42. Such a direct interaction targeting the monomer, dimer, and trimer suppressed further oligomerization. In contrast, the corresponding congeners without carboxy groups failed to do so.

Detection of Amyloid β Oligomers with RNA Aptamers in AppNL-G-F/NL-G-F Mice: A Model of Arctic Alzheimer’s Disease

“…Avoiding the disruption of noncovalent interactions among Aβ oligomers by not using organic solvents enabled us to observe the near-native status of Aβ oligomers in the presence of aggregation inhibitors. 39 After deconvolution based on the observed mass, peaks corresponding to oligomeric orders of Aβ42 and Aβ42-RNA adducts were assigned to the series of multivalent ions depending on their drift time ( Table S1 ). n denotes an integer corresponding to the number of units coexisting in the solution [ n = 1, 2, 3, ... denotes monomer (Mon), dimer (Dim), trimer (Tri), ..., respectively].…”

“…Mass spectra and ion mobility experiments were accomplished on a SYNAPT G2-Si HDMS (Waters) using a nanoelectrospray as an ionization source, as reported previously. 39 The instrument was operated in negative ion mode with a capillary voltage of 1.0 kV, a sample cone voltage of 10 V, and a source temperature of 50 °C. For the ion mobility measurement, nitrogen gas was used in the ion mobility cell, and the cell pressure was maintained at approximately 2.95 mbar with a wave velocity of 300–1000 m/s and a wave height of 10–40 V. Data acquisition and processing were performed with the MassLynx (V4.1) and DriftScope (V2.8) software supplied with the instrument.…”

Three Structural Features of Functional Food Components and Herbal Medicine with Amyloid β42 Anti-Aggregation Properties

“…To evaluate Aβ42 aggregation, a sequential-type aggregation test using Aβ42 treated with 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), known as an α-helix inducer to dissociate β-sheet-contained nuclei [35], is useful. It must be noted that HFIP-treated Aβ42 forms a α-helix structure (but not a random structure) even before aggregation [36]. Indeed, Hiroaki and coworkers raised the problem that HFIP usage is not enough to dissolve Aβ42 nuclei into monomers (remaining as dimers) based on NMR studies [37].…”

“…The structure–activity studies of uncarinic acid C (Figure 4a), which is able to prevent Aβ42-associated neurotoxicity, showed both a C-27 ferulate and a C-28 carboxylic acid group to be important for its inhibitory activities. According to SOFAST HMQC in NMR and ion mobility–mass spectrometry (IM-MS) combined with native ionization techniques, these inhibitor activities could be associated with the formation of a salt bridge with Lys16, resulting in the prevention of dimer or trimer formation, which can be a possible minimum unit of toxic oligomers (2 or 3 x n -mer) [36]. The flatness derived from C-27 ferulate may also participate in the interaction with either monomeric Aβ42 or its aggregates.…”

“…To further investigate the contribution of the carbon skeleton with a carboxy group, asiatic acid (ursane-type triterpenoid skeleton) from Centella asiatica in gotu kola and rhein (anthraquinoid skeleton) from Rheum palmatum in daio were selected together with α-amyrin and chrysophanic acid as the corresponding comparators [36] (Figure 4b). Asiatic acid retarded the nucleation of Aβ42, also focusing on the dimer or trimer, despite lacking a ferulate moiety.…”