Wang Yulu, Ge Yunzhi, Hua Siyu, Shen Chenrui, Cai Biao, Zhao Han
College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.
Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.
CNS Neurosci Ther. 2025 Mar;31(3):e70346. doi: 10.1111/cns.70346.
Impaired mitophagy results in the accumulation of defective mitochondria that are unable to be cleared effectively in Alzheimer's disease (AD). Aloe-emodin (AE), a key component of the traditional Chinese medicine Rhubarb, exhibits neuroprotective effects against Alzheimer's disease, though the underlying mechanism remains unclear. Studying aloe-emodin's role in enhancing mitophagy is vital for improving cognitive function and reducing neuronal damage in Alzheimer's disease.
The APP/PS1 double transgenic mice were adopted as models for AD to assess the effects of aloe-emodin upon cognitive function and its neuroprotective impact on hippocampal neurons. Additionally, we investigated the regulatory mechanisms of proteins within the aforementioned pathway, and the morphological characteristics of mitophagy-related proteins. An AD hippocampal neuron model was developed using Aβ25-35 to evaluate the mitochondrial function, the protein expression of such a pathway and the mitophagy. This approach aims to elucidate the effects and underlying mechanisms of aloe-emodin in relation to AD.
AE activates mitophagy in neurons, improves cognitive dysfunction, reduces hippocampal damage, and alleviates AD symptoms in model mice. AE activates the expression of AMPK, PGC-1α and SIRT3. Increased expression of SIRT3 in mitochondria promotes mitophagy and regulates the function of mitochondrial proteins. When mitochondrial autophagy is enhanced, the expression of Beclin1, LC3, P62, Parkin, and PINK1-related proteins changes. Further in vitro experiments showed that AE can enhance mitochondrial function in Alzheimer's disease cell models. The mitochondrial membrane potential, GSH, ROS and Ca2+ levels gradually recover, alleviating the pathological manifestations of AD. Knocking down SIRT3 leads to increased mitochondrial damage and a reduction in mitophagy in HT22 cells.
Experimental results show that AE can activate mitophagy through AMPK/PGC-1α/SIRT3 pathway, alleviate cognitive dysfunction in AD, and reduce damage to hippocampal neurons.
线粒体自噬受损会导致缺陷线粒体积累，而在阿尔茨海默病（AD）中这些缺陷线粒体无法被有效清除。芦荟大黄素（AE）是中药大黄的关键成分，对阿尔茨海默病具有神经保护作用，但其潜在机制尚不清楚。研究芦荟大黄素在增强线粒体自噬中的作用对于改善阿尔茨海默病的认知功能和减少神经元损伤至关重要。
采用APP/PS1双转基因小鼠作为AD模型，评估芦荟大黄素对认知功能的影响及其对海马神经元的神经保护作用。此外，我们研究了上述通路中蛋白质的调控机制以及线粒体自噬相关蛋白质的形态特征。使用Aβ25-35建立AD海马神经元模型，以评估线粒体功能、该通路的蛋白质表达和线粒体自噬。该方法旨在阐明芦荟大黄素与AD相关的作用及潜在机制。
AE激活神经元中的线粒体自噬，改善认知功能障碍，减少海马损伤，并减轻模型小鼠的AD症状。AE激活AMPK、PGC-1α和SIRT3的表达。线粒体中SIRT3表达增加可促进线粒体自噬并调节线粒体蛋白质的功能。当线粒体自噬增强时，Beclin1、LC3、P62、Parkin和PINK1相关蛋白的表达会发生变化。进一步的体外实验表明，AE可增强阿尔茨海默病细胞模型中的线粒体功能。线粒体膜电位、谷胱甘肽、活性氧和钙离子水平逐渐恢复，减轻了AD的病理表现。敲低SIRT3会导致HT22细胞中线粒体损伤增加和线粒体自噬减少。
实验结果表明，AE可通过AMPK/PGC-1α/SIRT3通路激活线粒体自噬，减轻AD的认知功能障碍，并减少对海马神经元的损伤。
