Ligustilide-loaded liposome ameliorates mitochondrial impairments and improves cognitive function via the PKA/AKAP1 signaling pathway in a mouse model of Alzheimer's disease

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2023-09-17 DOI:10.1111/cns.14460

Qi Zhang, Xiangxiang Zhang, Bing Yang, Yan Li, Xue-Heng Sun, Xiang Li, Ping Sui, Yi-Bin Wang, Shu-Yu Tian, Chun-Yan Wang

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引用次数: 0

Abstract

Background

Oxidative stress is an early event in the development of Alzheimer's disease (AD) and maybe a pivotal point of interaction governing AD pathogenesis; oxidative stress contributes to metabolism imbalance, protein misfolding, neuroinflammation and apoptosis. Excess reactive oxygen species (ROS) are a major contributor to oxidative stress. As vital sources of ROS, mitochondria are also the primary targets of ROS attack. Seeking effective avenues to reduce oxidative stress has attracted increasing attention for AD intervention.

Methods

We developed liposome-packaged Ligustilide (LIG) and investigated its effects on mitochondrial function and AD-like pathology in the APPswe/PS1dE9 (APP/PS1) mouse model of AD, and analyzed possible mechanisms.

Results

We observed that LIG-loaded liposome (LIG-LPs) treatment reduced oxidative stress and β-amyloid (Aβ) deposition and mitigated cognitive impairment in APP/PS1 mice. LIG management alleviated the destruction of the inner structure in the hippocampal mitochondria and ameliorated the imbalance between mitochondrial fission and fusion in the APP/PS1 mouse brain. We showed that the decline in cAMP-dependent protein kinase A (PKA) and A-kinase anchor protein 1 for PKA (AKAP1) was associated with oxidative stress and AD-like pathology. We confirmed that LIG-mediated antioxidant properties and neuroprotection were involved in upregulating the PKA/AKAP1 signaling in APPswe cells in vitro.

Conclusion

Liposome packaging for LIG is relatively biosafe and can overcome the instability of LIG. LIG alleviates mitochondrial dysfunctions and cognitive impairment via the PKA/AKAP1 signaling pathway. Our results provide experimental evidence that LIG-LPs may be a promising agent for AD therapy.

Abstract Image

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在阿尔茨海默病小鼠模型中，通过 PKA/AKAP1 信号通路，利格列脂质体可改善线粒体损伤并提高认知功能。

背景：氧化应激是阿尔茨海默病（AD）发生发展的早期事件，可能是影响阿尔茨海默病发病机制的关键相互作用点；氧化应激导致新陈代谢失衡、蛋白质错误折叠、神经炎症和细胞凋亡。过量的活性氧（ROS）是造成氧化应激的主要因素。作为 ROS 的重要来源，线粒体也是 ROS 攻击的主要目标。寻求减少氧化应激的有效途径已引起人们对AD干预的日益关注：方法：我们开发了脂质体包装的藁本内酯（LIG），并研究了其对APPswe/PS1dE9（APP/PS1）小鼠AD模型线粒体功能和AD样病理的影响，并分析了可能的机制：结果：我们观察到，LIG负载脂质体（LIG-LPs）治疗减少了氧化应激和β淀粉样蛋白（Aβ）沉积，减轻了APP/PS1小鼠的认知障碍。LIG管理减轻了海马线粒体内部结构的破坏，改善了APP/PS1小鼠大脑线粒体裂变和融合之间的不平衡。我们发现，cAMP 依赖性蛋白激酶 A（PKA）和 PKA 的 A- 激酶锚定蛋白 1（AKAP1）的减少与氧化应激和类似 AD 的病理变化有关。我们证实，LIG介导的抗氧化特性和神经保护作用参与了体外APPswe细胞中PKA/AKAP1信号的上调：结论：LIG的脂质体包装具有相对的生物安全性，可以克服LIG的不稳定性。LIG通过PKA/AKAP1信号通路缓解线粒体功能障碍和认知障碍。我们的研究结果提供了实验证据，证明LIG-LPs可能是一种治疗AD的有效药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.