Front Aging Neurosci︱Ma Tao's team reveals the mechanism of Chinese herbal compound multi-pathway and multi-target improving energy metabolism in Alzheimer's disease

Written by ︱Han Guanghui, Zhen Weizhe editors︱Wang Sizhen Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and the most important form of senile dementia
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The pathogenesis of AD is complex, involving multiple pathways and links, and there is still no effective treatment [1]
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As the organ with the most energy demand and consumption, the brain is particularly sensitive to energy metabolism disorders
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Energy metabolism disorder is also one of the important pathological events in the early stage of AD, and it is a potential effective target for AD treatment, so it has become the focus of international research [2]
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Traditional Chinese medicine compounds have the characteristics of multi-component, multi-channel and multi-target action, and show good clinical efficacy and application potential in long-term clinical practice
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Dihuang Yinzi (Dihuang-Yinzi) is a traditional Chinese medicine compound.
It is from "Huangdi Suwen·Xuanming Lunfang" by Liu Wansu, a famous medical expert in the Jin Dynasty.
It has been used for a long time in the treatment of neurodegenerative diseases including AD [3]
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However, the integrated action mechanism of Dihuangyinzi in the treatment of AD with multiple pathways and multiple targets is still unclear
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 On April 1, 2022, Ma Tao's team from Dongfang Hospital (Second Clinical Medical College) of Beijing University of Traditional Chinese Medicine published an online publication entitled "Dihuang-Yinzi Alleviates Cognition Deficits via Frontiers in Aging Neuroscience".
"Targeting Energy-Related Metabolism in an Alzheimer Mouse Model as Demonstrated by Integration of Metabolomics and Network Pharmacology" research paper
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Han Guanghui, Zhen Weizhe, and Dai Yuan are the co-first authors of the paper, and Ma Tao is the corresponding author of the paper
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This study integrates network pharmacology, metabolomics and molecular biology research techniques, and confirms that Dihuangyinzi can exert multi-pathway and multi-target effects by regulating 4 energy-related metabolic pathways, 5 key target proteins and 14 differential metabolites.
The core link of its mechanism of action against AD is the protection of mitochondrial structure and function
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At the same time, this study provides a useful attempt to explore the research paradigm of the mechanism of traditional Chinese medicine in the treatment of complex diseases
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First of all, the researchers confirmed through behavioral experiments that Dihuang Yinzi can shorten the escape latency of Morris water maze test in APP/PS1 mice and increase the number of crossing the platform area
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The results showed that Dihuang Yinzi could significantly improve the spatial learning and memory ability of APP/PS1 mice (Figure 1)
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Figure 1 The improvement effect of Dihuangyinzi on spatial learning and memory in APP/PS1 mice (Source: Han G et al.
, Front Aging Neurosci, 2022) The researchers then used network pharmacology analysis and found that Dihuangyinzi can treat AD of 192 potential targets
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Through the construction of PPI network, 15 key target genes of Dihuang Yinzi in the treatment of AD were screened, including NDUFA12, NDUFS1, GAPDH, IL10, AKT1, SIRT1, HIF1A, NOS3, HSPA1A, PARP1, ARG1, LDHA, ACHE, ALDH3B2, DAO, etc.

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GO and KEGG analysis found that the above 192 therapeutic targets were mainly related to energy metabolism, oxidative damage, protection of mitochondrial function, oxidative phosphorylation, oxidoreductase system, etc.
, mainly involving neurodegenerative diseases such as AD, PD and HD (Fig.
2)
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Figure 2 Network pharmacology analysis of Dihuangyinzi for AD treatment (Source: Han G et al.
, Front Aging Neurosci, 2022) Through non-targeted metabolomic analysis, 22 APP/PS1 mice treated with Dihuangyinzi were screened different metabolites
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Through cluster analysis, the researchers found that the main metabolic pathways involved in these differential metabolites include tricarboxylic acid (TCA) cycle, pyruvate metabolism, glycolysis/gluconeogenesis, arginine biosynthesis, niacin, nicotinamide metabolism and glycerophospholipid metabolism, etc.
(Figure 3)
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Figure 3 Non-targeted metabolomic analysis of Dihuangyinzi intervention in APP/PS1 mice (source: Han G et al.
, Front Aging Neurosci, 2022) In order to systematically analyze the effect of Dihuangyinzi on the metabolism of APP/PS1 mice Through the combined analysis of metabolomics and network pharmacology, the researchers constructed a "metabolite-reaction-enzyme-gene" action network of Dihuang Yinzi intervening in APP/PS1 mice (Figure 4)
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Through action network analysis, the researchers found: 5 protein targets including DAO, HIF1A, ALDH3B2, PARP1 and ACHE, 14 differential metabolites such as pyruvate and L-lactate, and TCA cycle, glycolysis, niacin/nicotinamide Four metabolic pathways including metabolism and glycerophospholipid metabolism play key roles in the intervention of Dihuang Yinzi on APP/PS1 mice
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Figure 4 Metabolomics and network pharmacology interaction network of Dihuangyinzi intervention in APP/PS1 mice (Source: Han G et al.
, Front Aging Neurosci, 2022) Acetylcholine (Ach) is the most closely related to learning and memory.
A close neurotransmitter, it is one of the important metabolites of glycerophospholipid metabolism
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In order to verify the above joint analysis results, the researchers confirmed that Dihuang Yinzi can down-regulate the expression of acetylcholinesterase (AchE) and increase the level of Ach in the brain of APP/PS1 mice (Figure 5)
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Cardiolipin (CL) is the most important phospholipid component on the inner mitochondrial membrane and a key metabolite in glycerophospholipid metabolism
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The researchers confirmed that Dihuang Yinzi could significantly increase the level of phospholipids in the brain of APP/PS1 mice
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In view of the close relationship between cardiolipin and mitochondrial inner membrane integrity and its function, the researchers further found that Dihuangyinzi can significantly improve the damage of mitochondrial structure in the brain tissue of APP/PS1 mice, reduce mitochondrial swelling, and increase mitochondrial membrane potential and mitochondrial internalization.
Membrane respiratory chain complex activity reduces ROS release (Fig.
5)
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These results indicated that Dihuangyinzi increased Ach and cardiolipin levels in the brain of APP/PS1 mice, improved mitochondrial structure and function, and reduced ROS release by regulating glycerophospholipid metabolism
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Figure 5 Dihuang Yinzi improves mitochondrial structure and function by regulating glycerophospholipid metabolism in APP/PS1 mice (Source: Han G et al.
, Front Aging Neurosci, 2022) According to the combined analysis, niacin/nicotinamide metabolism and glycolysis It is the key way for Dihuangyinzi to treat APP/PS1 mice
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The researchers confirmed that Dihuang Yinzi can significantly increase the levels of niacin, nicotinamide and NAD+, down-regulate the expression of PARP-1, and then improve the metabolism of niacin/nicotinamide in APP/PS1 mice
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Dihuangyinzi can also up-regulate the expression of ALDH3B2, a key protein in glycolysis
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In addition, the researchers found that ALDH3B2 co-localized with astrocyte-specific marker S100B, confirming that ALDH3B2 is specifically expressed in astrocytes, and glycolysis is mainly completed in astrocytes, thus further It was confirmed that Dihuangyinzi could improve glycolysis in APP/PS1 mice (Figure 6)
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Figure 6 Dihuangyinzi improves niacin/nicotinamide metabolism and glycolysis pathway in APP/PS1 mice (Source: Han G et al.
, Front Aging Neurosci, 2022) The energy required for the physiological activities of the central nervous system is mainly from mitochondria Provided by the TCA cycle and its coupled oxidative phosphorylation
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The researchers further confirmed that Dihuang Yinzi could reduce the levels of pyruvic acid, citric acid, succinic acid and fumaric acid that were elevated due to the blocked TCA cycle in APP/PS1 mice
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In the pathogenesis of AD, HIF1A can up-regulate pyruvate dehydrogenase kinase 1 (PDHK1), which in turn promotes the phosphorylation of pyruvate dehydrogenase (PDH) and inhibits the entry of pyruvate into the TCA cycle, resulting in the blockage of the TCA cycle
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The researchers confirmed that Dihuangyinzi down-regulated the expression of HIF1A and PDHK1 in APP/PS1 mice, inhibited the phosphorylation of PDH, thereby promoting the TCA cycle, improving energy metabolism, and increasing the level of energy charge in the brain tissue of APP/PS1 mice (Figure 7)
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Figure 7 Dihuang Yinzi improves TCA circulation and brain energy charge in APP/PS1 mice (Source: Han G et al.
, Front Aging Neurosci, 2022) Conclusion and discussion, inspiration and prospect Metabolomics, network pharmacology and experimental verification, aiming at the metabolic process in vivo, systematically explore the mechanism of action of Dihuang Yinzi in the treatment of Alzheimer's disease (AD)
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The researchers used the network pharmacology method to explore the potential targets of Dihuangyinzi in the treatment of AD, and performed metabolomic analysis of the urine differential metabolites of Dihuangyinzi intervened in APP/PS1 mice
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Through the combined analysis of network pharmacology and metabolomics, the researchers found that the traditional Chinese medicine compound Dihuangyinzi can exert its anti-AD therapeutic effect in a multi-channel and multi-target manner, which involves four metabolic pathways closely related to energy metabolism.
Includes glycerophospholipid metabolism, niacin/nicotinamide metabolism, glycolysis, and the tricarboxylic acid cycle
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At the same time, the researchers further screened out five key targets of Dihuang Yinzi regulating energy metabolism, including DAO, HIF1A, PARP1, ALDH3B2 and ACHE
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The aforementioned energy metabolism pathways affected the levels of 14 differential metabolites
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The above pathways, targets and metabolites are all centered on mitochondrial structure and function
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In this study, the method of combined analysis was used to reveal and confirm the multi-path and multi-target action characteristics of the traditional Chinese medicine compound Dihuang Yinzi in the treatment of AD
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This work provides a useful exploration for the study of the mechanism of action of multi-component traditional Chinese medicine compounds in the treatment of complex diseases, and provides a beneficial research approach for explaining the multi-channel and multi-target action modes of traditional Chinese medicine compounds
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In future research, using multi-omics analysis methods to explain the mechanism of action of traditional Chinese medicine compounds on complex diseases such as Alzheimer's disease deserves more attention and energy from researchers
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Link to the original text: https:// Authors of the article from left to right: Co-first authors Han Guanghui (first from left), Zhen Weizhe (second from left), Dai Yuan (third from left) ); Corresponding author Ma Tao (first from the right) (Photo courtesy of: Ma Tao's Laboratory, Oriental Hospital, Beijing University of Traditional Chinese Medicine) This paper was funded by the National Natural Science Foundation of China (81973786, 81673929)
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The main research direction of Ma Tao's team is the pathogenesis of Alzheimer's disease and the prevention and treatment of traditional Chinese medicine
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Introduction to Ma Tao's team website: https://
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