Oxidative stress is an important pathogenic manifestation of Alzheimer’s disease (AD) that contributes to synaptic dysfunction, which precedes Aβ accumulation and neurofibrillary tangle formation. However, the molecular machineries that govern the decline of antioxidative defence in AD remains to be elucidated, and effective candidate for AD treatment is limited. Here, we showed that the decreases in the inhibitor of apoptosis-stimulating protein of p53 (iASPP) was associated with the vulnerability to oxidative stress in the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse brain. Treatment with an antioxidant, syringin, could ameliorate AD-related pathologic and behavioural impairments. Interestingly, syringin treatment resulted in an upregulation of iASPP and the increase in the interaction of iASPP with Kelchlike ECH-associating protein 1 (Keap1). Syringin reduced neuronal apoptosis independently of p53. We confirmed that syringin-induced enhancement of antioxidant defenses involved the stabilization of Nrf2 in overexpressing human Swedish mutant APP (APPswe) cells in vitro. Syringin-mediated Nrf2 nuclear translocation facilitated the activation of the Nrf2 downstream genes via iASPP/Nrf2 axis. Our results demonstrate that syringin-mediated increases of iASPP-Keap1 interaction restore cellular redox balance. Further study on the syringin-iASPP interactions may help in understanding the regulatory mechanism and designing novel potent modulators for AD treatment.Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.