Tangeretin (TAN) exhibits many bioactivities, including neuroprotective effects. However, the efficacy of TAN in Alzheimer’s disease (AD) has not been sufficiently investigated. In the present study, we integrated behavioral tests, pathology assessment, and biochemical analyses to elucidate the antidementia activity of TAN in APPswe/PSEN1dE9 transgenic (Tg) mice. At supplementation levels of 100 mg/kg body weight per day, TAN significantly attenuated the cognitive impairment of Tg mice in behavioral tests. These effects were associated with less synaptic impairments and fewer β-amyloid accumulations after TAN administration. Furthermore, our study revealed that TAN possessed powerful inhibitory activity against β-secretase both in vitro and in vivo, which played a crucial role in the process of Aβ generation. These findings indicate that TAN is a potential drug for preventing AD pathology. The key mechanism underlying the antidementia effect of TAN may include its inhibitory activity against β-secretase.
