Teng et al. (2010) observed that activating DOR enhanced the activity of β-site-APP cleaving enzyme 1 (BACE1) and γ-secretase, increasing the production of Aβ in 293T cells. Using a more specific and potent DOR agonist in the neuron-like model (PC12 cells), we have recently shown that DOR activation decreased the expression and activity of BACE1, reducing the production of toxic Aβ (Xu et al., 2020a). Furthermore, we found that the activation of DOR reduced the deposition of Aβ plaques in the cortex and hippocampus and improved cognitive impairment in APP/PS1 mice (Xu et al., 2025). Here, BACE1 is linked to Cognitive impairment.