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.

Qinru Sun,Xin Li,Guomin Chen,Jie Yang,Ning Jia

doi:10.18632/aging.102041

Qinru Sun, Xin Li + Show 3 more

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https://doi.org/10.18632/aging.102041

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Journal: Aging (Albany NY)	Publication Date: Jun 24, 2019
Citations: 29	License type: cc-by

Affiliation: Xi'an Jiaotong University

Abstract

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.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive function and an irreversible loss of neurons [1, 2]
LY294002 preserved intracellular reactive oxygen species (ROS) production when co-cultured with Grape seed proanthocyanidins (GSPs) in the presence of STZ. These results indicate that GSPs can counteract STZ-induced neuron loss and oxidative stress in primary cortical neurons by activating the phosphatidylinositol 3-kinase (PI3K) pathway
The main findings of the present study indicate that GSPs ameliorate neuronal oxidative damage and cognitive impairments in AD by inhibiting glycogen synthase kinase 3β (GSK-3β)-dependent mitochondrial permeability transition pore (mPTP) opening

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive function and an irreversible loss of neurons [1, 2]. In AD brains, the accumulated extracellular senile plaques, consisting predominantly of the amyloidβ (Aβ), and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein, are neuropathological hallmarks [4]. Both senile plaques and neurofibrillary lesions seem to result in neuronal loss in affected brain areas. In addition to transgenic animals used to study FAD, rat or mouse subjected to intracerebroventricular (ICV) injections of streptozotocin (STZ) become a feasible and workable model for revealing the mechanisms of SAD or screening medicines [6, 7]. These related studies have suggested that there are some common features between FAD and SAD, such as mitochondrial dysfunction [8] and oxidative stress [9, 10]

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