Research Paper Volume 11, Issue 12 pp 4107—4124
Grape seed proanthocyanidins ameliorate neuronal oxidative damage by inhibiting GSK-3β-dependent mitochondrial permeability transition pore opening in an experimental model of sporadic Alzheimer’s disease
- 1 Institute of Forensic Medicine, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P.R. China
- 2 Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi’an, Jiaotong University Health Science Center, Xi’an Shaanxi 710061, P.R. China
- 3 Department of Anesthesiology, First Affiliated Hospital, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P.R. China
received: September 19, 2018 ; accepted: June 17, 2019 ; published: June 24, 2019 ;https://doi.org/10.18632/aging.102041
How to Cite
Copyright: Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Mitochondria-associated oxidative stress plays a crucial role in Alzheimer’s disease (AD). Grape seed proanthocyanidins (GSPs) have been reported to prevent oxidative stress. In this study, we investigated the underlying mechanisms of GSPs in protecting neurons against oxidative injury in an experimental model of sporadic AD. Primary mouse cortical neurons were subjected to streptozotocin (STZ) to mimic neuronal oxidative damage in vitro, and mice were subjected to intracerebroventricular (ICV) injection of STZ as an in vivo sporadic AD model. GSPs not only significantly ameliorated neuron loss and mitochondrial dysfunction in mouse cortical neurons pretreated of STZ, but also reduced cognitive impairments, apoptosis and mitochondrial oxidative stress in the cerebral cortex and hippocampus of sporadic AD mice. Moreover, GSPs increased phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), Akt and glycogen synthase kinase 3β (GSK-3β) at its Ser9. Notably, GSPs inhibited STZ-induced mitochondrial permeability transition pore (mPTP) opening via enhancing phosphorylated GSK-3β (p-GSK-3β) binds to adenine nucleotide translocator (ANT), thereby reducing the formation of the complex ANT-cyclophilin D (CypD). In conclusion, GSPs ameliorate neuronal oxidative damage and cognitive impairment by inhibiting GSK-3β-dependent mPTP opening in AD. Our study provides new insights into that GSPs may be a new therapeutic candidate for treatment of AD.
AD: Alzheimer’s disease; ANT: adenine nucleotide translocator; APP: amyloid precursor protein; ATP: adenosine triphosphate; β-amyloid: (Aβ); CcO: cytochrome c oxidase; CsA: cyclosporin A; CypD: cyclophilin D; FAD: family Alzheimer’s disease; GSPs: Grape seed proanthocyanidins; GSK-3β: glycogen synthase kinase 3β; ICV: intracerebroventricular; HD: Huntington’s disease; HED: human equivalent dose; H2DCFDA: 2’,7’-Dichlorofluorescin diacetate; MMP: mitochondrial membrane potential; mPTP: mitochondrial permeability transition pore; MTT: (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MWM: Morris Water Maze; NFTs: neurofibrillary tangles; p-GSK-3β: phosphorylated GSK-3β; OD540nm: optical density 540 nm; PBS: phosphate-buffered saline; p-GSK-3β: phosphorylated glycogen synthase kinase 3β; p-tau: phosphorylated tau; PI3K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SAD: sporadic Alzheimer’s disease; STZ: streptozotocin; TUNEL: TdT-mediated dUTP Nick-End Labeling.