Naringin ameliorates Alzheimer’s disease-like cognitive impairment through coordinated NF-κB/Nrf2 pathway modulation

Alzheimer’s disease (AD) is driven by interacting pathological processes, including amyloid-β (Aβ) accumulation, oxidative stress, synaptic dysfunction and chronic neuroinflammation. Naringin, a citrus flavanone glycoside, has reported antioxidant and anti-inflammatory activity; however, the pathway dependence of its neuroprotective effects remains incompletely defined. In this study, naringin was evaluated in Aβ1-42-challenged neuronal cultures and in APP/PS1 transgenic mice. Naringin improved neuronal viability, reduced reactive oxygen species accumulation, restored mitochondrial membrane potential and attenuated apoptosis. These effects were accompanied by enhanced Nrf2/ARE activity and suppression of NF-κB activity. Nrf2 knockdown or pharmacological inhibition markedly weakened naringin-mediated protection, whereas constitutively active p65 partially reversed its anti-inflammatory effect. In APP/PS1 mice, oral naringin improved spatial and recognition memory, reduced soluble and insoluble Aβ, decreased glial activation and pro-inflammatory cytokine production, restored synaptic markers and enhanced hippocampal long-term potentiation. Brain-exposure analysis detected naringenin, the principal aglycone metabolite, in hippocampal tissue after chronic dosing. These findings illustrate a coherent preclinical manuscript model in which naringin improves AD-like phenotypes through coordinated suppression of NF-κB-dependent neuroinflammation and activation of Nrf2-mediated antioxidant defence.