Ligustilide Ameliorates Memory Deficiency in APP/PS1 Transgenic Mice via Restoring Mitochondrial Dysfunction.

Yi-Jun Xu,Yong-Bin Zhang,Zi-Ling Qu,Si-Jun Liu,Cong Yang,Jun Wu,Yu Mei,Shi-Jie Zhang,Qi Wang,Wei Zhao,Jian-Song Fang,Yong-Qi Fang

doi:10.1155/2018/4606752

Yi-Jun Xu, Yong-Bin Zhang + Show 10 more

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https://doi.org/10.1155/2018/4606752

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Abstract

Ligustilide, the main lipophilic component of Radix angelicae sinensis, has been shown to ameliorate cognitive dysfunction in a few Alzheimer's disease mouse models, but its mechanism is not fully understood. In this study, we employed 7-month-old APP/PS1 mice to explore whether LIG is able to protect against Alzheimer's disease progression. The Morris water maze and Y-maze test results showed that eight weeks of intragastric administration of LIG (10 mg/kg, 40 mg/kg) every day improved memory deficit in APP/PS1 mice. The thioflavin-S staining and Western blot results (Aβ1-42 monomer/oligomer, APP, ADAM10, SAPPα, and PreP) showed that LIG reduced Aβ levels in the brain of APP/PS1 mice. Transmission electron microscopy analysis showed that LIG reduced the mitochondria number and increased the mitochondrial length in the hippocampal CA1 area of APP/PS1 mice. A reduced level of Drp1 (fission) and increased levels of Mfn1, Mfn2, and Opa1 (fusion) were found in APP/PS1 mice treated with LIG. An increased ATP level in the brain and increased activities of cytochrome c oxidase (CCO) and succinate dehydrogenase (SDH) in mitochondrion separated from the hippocampus and cortex revealed that LIG alleviated mitochondrial dysfunction. LIG exerts an antioxidation effect via reducing the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and increasing the activity of Mn-SOD in the brain. Elevated levels of PSD-95, synaptophysin, and synapsin 1 in both the hippocampus and cortex indicated that LIG provided synaptic protection. These findings show that treatment with LIG ameliorates mitochondrial dynamics and morphology issues, improves mitochondrial function, reduces Aβ levels in the brain, restores the synaptic structure, and ameliorates memory deficit in APP/PS1 mice. These results imply that LIG may serve as a potential antidementia drug.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease in the elderly population and is characterized by amyloid plaque deposition and distinct neuronal loss in the brain, resulting in progressive impairment of cognition [1]
Primary antibodies against amyloid precursor protein (APP), a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), BACE1, neprilysin (NEP), insulin-degrading enzyme (IDE), presequence protease (PreP), presenilin 1 (PS1), human soluble amyloid precursor protein alpha (SAPPα), human soluble amyloid precursor protein β (SAPPβ), and dynaminrelated protein 1 (Drp1) were purchased from Cell Signaling Technology, Inc
The APP/PS1 group spent less time spent in the target quadrant (p < 0.01), made fewer attempts to traversing the removed platform position (p < 0.05), and had more chaotic swimming paths

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease in the elderly population and is characterized by amyloid plaque deposition and distinct neuronal loss in the brain, resulting in progressive impairment of cognition [1]. Several AD pathologies, such as mitochondrial dysfunction and synaptic loss, are closely related to Aβ overexpression [5,6,7]. Mitochondria are energy production organelles that mediate cell respiratory processes, free radical production, and metabolism [8]. The rates of fusion and fission are balanced [9]. Mitochondria can travel along axons, dendrites, and synapses to supply the necessary energy for synaptic functions, such as neurotransmitter release and synapse formation [10]. Aβ is transported into mitochondria via the mitochondrial outer membrane

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