期刊
REDOX BIOLOGY
卷 36, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2020.101672
关键词
Alzheimer's disease; Oxidative stress; iASPP/Nrf2 axis; Syringin; Synaptic plasticity; Amyloid pathology
资金
- Natural Science Foundation of China [81671041, 81971026]
- Natural Science Foundation of Liaoning Provincial Science & Technology Department in China [2018225086, 20180550924]
- Natural Science Foundation of Jilin Provincial Educational Department in China [JJKH20200455KJ]
Oxidative stress is an important pathogenic manifestation of Alzheimer's disease (AD) that contributes to syn-aptic dysfunction, which precedes A beta accumulation and neurofibrillary tangle formation. However, the molec-ular 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.
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