A Unified View of Assessing the Pro‐oxidant versus Antioxidant Nature of Amyloid Beta Conformers

Abstract

Transition-metal-catalyzed oxidative stress is a widespread concern in the pathogenesis of Alzheimer's disease. However, the exact role of amyloid beta oligomers towards oxidative stress is widely debated. Assessing the oxidative nature of the oligomers in vitro is complicated by the different experimental conditions under which they are prepared. We have investigated Cu -catalyzed reactive oxygen species (ROS) generation by using oligomers prepared in phosphate-buffered saline (Aβ ) and in cell culture medium (Aβ ), and compared their activities with respect to the monomers and fibrils prepared at neutral and acidic pH. Although both are deca- to dodecamers, the Aβ oligomers have a spherical morphology and are smaller than the Aβ . The Aβ behaved as pro-oxidants; in contrast, Aβ quench OH generation attributed to CCM itself. Although the pro-oxidant oligomers showed oxidation, they also partially protect themselves from radical damage and maintain their overall spherical arrangement. The monomers and fibrils manifested antioxidant properties: radical scavenging as opposed to redox silencing. A dual role of Aβ species depending on the stage of the disease is proposed. In the earlier stages, the monomers can act as antioxidants, whereas at the later stages, the oligomers take on a pro-oxidant role. Kaempferol, a natural flavonoid, bound Cu in 2:1 ratio and abolished ROS production in all Aβ species. It also distinctly modified the folding landscape of Aβ species into new or altered morphologies.

Rational Design of a Cu Chelator That Mitigates Cu‐Induced ROS Production by Amyloid Beta

“…by coumarin‐3‐carboxylic acid (3‐CCA) assay. Consistent with our previous results, [50] we find that the degree of ROS generation is dependent on the aggregation state of Aβ 42 . As seen from the Asc oxidation presented in Figure 2A–C, the Aβ O−PBS (Figure 2B, black) consumed Asc the fastest compared to the monomers (Aβ M ) (Figure 2A, black), fibrils (Aβ F−PBS ) (Figure 2C, black), and free Cu 2+ in solution (Figure 2A, orange).…”

“…The chelator should also bind both redox states of Cu, redox silence Cu, and kinetically remove Cu 2+ faster from the Cu−Aβ complex [49] . In this regard, several natural products, [50–52] peptide‐based inhibitors, [26,28] and synthetic molecules [38,40,53,54] have been investigated to mitigate the effect of Aβ‐induced AD pathogenesis.…”

“…In our previous report, we probed the antioxidant versus pro‐oxidant role of different types of Aβ 42 conformers towards Cu‐catalyzed ROS generation [50] . We found that the oligomers prepared in phosphate buffer saline (PBS) (Aβ O−PBS ) generated more ROS than the monomers and fibrils.…”

Amyloid-Beta Peptides and Activated Astroglia Impairs Proliferation of Nerve Growth Factor Releasing Cells In Vitro: Implication for Encapsulated Cell Biodelivery-Mediated AD Therapy

“…Although Aβ peptides are incapable of inducing cell death at a <5 μM concentration [ 21 , 31 ] ( Figure 2 ), they can significantly induce inflammatory responses from ARPE cells, leading to degeneration and accelerated senescence [ 32 , 33 ]. Surprisingly, Aβ peptides were not found to induce oxidative stress in NGC0211 cells, which may be attributed to the antioxidant properties of soluble Aβ [ 34 , 35 ]. Nonetheless, we showed that Aβ peptides and inflammatory molecules, such as IL-1β and TNFα, can severely impair NGC0211 cell proliferation when exposed directly ( Figure 3 , Figure S5B ).…”

Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration

“…As mentioned above, ROS facilitate the formation of neurofibrillary tangles by promoting the misfolding and cross-linking of proteins [ 23 , 47 , 48 ]. Some studies reported the potential role of Aβ monomers as antioxidants, depending on the metal ion concentration in vitro [ 49 , 50 ]. In contrast, other studies showed that oligomeric Aβ, the dominant form in patients with AD, promotes ROS production in cooperation with metal ions in vitro and in vivo [ 51 , 52 , 53 , 54 ].…”