Alzheimer's disease (AD) is primarily driven by the formation of toxic amyloid-β (Aβ) aggregates, with Aβ42 being a pivotal contributor to disease pathology. This study investigates a novel agent to mitigate Aβ42-induced toxicity by co-assembling Aβ42 with its G37V variant (Aβ42(G37V)), where Gly at position 37 is substituted with valine. Using a combination of Thioflavin-T (Th-T) fluorescence assays, Western blot analysis, atomic force microscopy (AFM)/transmission electron microscopy (TEM), and biochemical assays, we demonstrated that adding Aβ42(G37V) significantly accelerates Aβ42 aggregation rate and mass while altering the morphology of the resulting aggregates. Consequently, adding Aβ42(G37V) reduces the Aβ42 aggregates-induced cytotoxicity, as evidenced by improved cell viability assays. The possible mechanism for this effect is that adding Aβ42(G37V) reduces the production of reactive oxygen species (ROS) and lipid peroxidation, typically elevated in response to Aβ42, indicating its protective effects against oxidative stress. These findings suggest that Aβ42(G37V) could be a promising candidate for modulating Aβ42 aggregation dynamics and reducing its neurotoxic effects, providing a new avenue for potential therapeutic interventions in AD.
Keywords: Aβ42; Aβ42(G37V); aggregation; glycine-zipper motif; morphology; toxicity.