Oxidative stress in the brain is highly related to the pathogenesis of Alzheimer’s disease (AD). It could be induced by the overproduction of reactive oxygen species (ROS), produced by the amyloid beta (Aβ) peptide and excess copper (Cu) in senile plaques and cellular species, such as ascorbic acid (AA) and O₂. In this study, the protective effect of 5-hydroxy-7-(4′-hydroxy-3′-methoxyphenyl)-1-phenyl-3-heptanone (DHPA) on Aβ_(1–42)/Cu²⁺/AA mixture-treated SH-SY5Y cells was investigated via in vitro and in silico studies. The results showed that DHPA could inhibit Aβ/Cu²⁺/AA-induced SH-SY5Y apoptosis, OH· production, intracellular ROS accumulation, and malondialdehyde (MDA) production. Further research demonstrated that DHPA could decrease the ratio of Bax/Bcl-2 and repress the increase of mitochondrial membrane potential (MMP) of SH-SY5Y cells, to further suppress the activation of caspase-3, and inhibit cell apoptosis. Meanwhile, DHPA could inhibit the Aβ/Cu²⁺/AA-induced phosphorylation of Erk1/2 and P38 in SH-SY5Y cells, and increase the expression of P-AKT. Furthermore, DHPA could bind to Keap1 to promote the separation of Nrf2 to Keap1 and activate the Keap1/Nrf2/HO-1 signaling pathway to increase the expression of heme oxygenase-1 (HO-1), quinone oxidoreductase-1 (NQO1), glutathione (GSH), and superoxide dismutase (SOD). Thus, our results demonstrated that DHPA could inhibit Aβ/Cu²⁺/AA-induced SH-SY5Y apoptosis via scavenging OH·, inhibit mitochondria apoptosis, and activate the Keap1/Nrf2/HO-1 signaling pathway.

Exosome-like nanovesicles (ELNs) derived from plants are nanoscale vesicles isolated from edible plant sources. Lycium ruthenicum Murray (LRM) has garnered growing attention for its dietary value and therapeutic benefits. In this study, a PEG6000-based method was developed to isolate LRM-ELNs. Response surface methodology (RSM) was used to optimize the extraction conditions to obtain the optimal extraction efficiency. When PEG6000 concentration was at 11.93%, relative centrifugal force was 9720 g, and incubation time was 21.12 h, the maximum LRM-ELN yield was 4.24 g/kg. This optimization process yielded LRM-ELNs with a particle size of 114.1 nm and a surface charge of −6.36 mV. Additionally, LRM-ELNs mitigated Aβ-induced apoptosis in HT22 cells by enhancing mitochondrial membrane potential (MMP), lowering the Bax/Bcl-2 ratio, and reducing Cleaved Caspase-3 expression. Furthermore, LRM-ELNs alleviated Aβ-induced oxidative stress in HT22 cells by promoting the nuclear translocation of Nrf2 and upregulating the expression of HO-1 and NQO1. These findings indicate that LRM-ELNs exert protective effects against Aβ-induced damage in HT22 cells and may be considered as a potential dietary supplement for Alzheimer’s disease prevention.