Red Ginseng Attenuates Aβ-Induced Mitochondrial Dysfunction and Aβ-mediated Pathology in an Animal Model of Alzheimer's Disease.

Soo Jung Shin,Yu-On Jeong,Seong Gak Jeon,Yunkwon Nam,Sujin Kim,Yong Ho Park,Minho Moon,Jwa-Jin Kim,Yong Yook Lee,Hyunhee Park,Hyeon Soo Kim,Sua Oh,Sang Bum Hong,Jong-Seok Kim,Ji-Young Hwang,Sun-Hyun Park,Seong-Kyung Lee,Hyun Ha Park,Jin-Il Kim

doi:10.3390/ijms20123030

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia, has a reported incidence of 50%–56% among dementia patients, and is a highly prevalent neurodegenerative disorder [1,2]
To determine the effects of RG extract (RGE) on Aβ-induced mitochondrial deficits, cultured HT22 cells were treated with Aβ (2 μM) and/or RGE (1, 10, and 100 μg/mL) and the oxygen consumption rate (OCR) was measured using the Seahorse XFp analyzer (Figure 1B)
The persistent OCR level noted after blocking the hydrogen ion gradient between the intermembrane space and mitochondrial matrix by addition of inhibitors of complex I and complex III represents non-mitochondrial respiration sustained by a subset of cellular enzymes

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia, has a reported incidence of 50%–56% among dementia patients, and is a highly prevalent neurodegenerative disorder [1,2]. The Aβ cascade hypothesis indicates that its progenitor peptide, amyloid precursor protein (APP), is sequentially cleaved by β-secretase and γ-secretase consecutively to produce Aβ [5,6]. These Aβ peptides induce neuroinflammation, neuronal loss, and alteration of adult neurogenesis [7,8]. ATP production is decreased in neurons, and Aβ-induced oxidative stress negatively affects neurotransmission, synaptic functions, and cognitive functions such as memory in AD patients [12,17]. It has been proposed that when mitochondrial dysfunction occurs, accumulation of Aβ increases, which might result in a vicious cycle that contributes to the onset and progression of AD. Preventing mitochondria from becoming a mediator of Aβ toxicity can be a key to AD therapy

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Conclusion