Alzheimer's disease (AD) is usually characterized by cognitive impairment, whose two typical pathological features are extracellular amyloid plaque and intracellular neurofibril entanglement. The number of AD patients is increasing with the advent of the aging era, and it has become one of the significant public health problems in the world (Meng F. C. et al., 2018; Beckman et al., 2021). Neuroinflammation, synaptic degeneration, oxidative stress, and loss of hippocampal neurons are important factors leading to AD (Kumar et al., 2015; Cai et al., 2016; Teruya et al., 2021). It is estimated that the number of patients may increase double in the coming decades due to the lack of effective prevention and proper treatment (Hebert et al., 2013; Scheltens et al., 2021). If the disease of AD is not controlled, it will directly impact human health and the social economy, and long-term care will also put a massive burden on the families of patients (Association, 2021). Donepezil, rivastigmine, galanthamine, and other drugs are used to interfere with the course of AD (Cai et al., 2016). They may improve poor memory, maintain basic communication skills, and address some uncontrollable behaviors in AD patients. However, these drugs have drawbacks, such as limited therapeutic efficacy and side effects (Mancuso et al., 2011). Today, medications have not been discovered to prevent cognitive impairment and improve memory, judgment, and communication skills (Zemek et al., 2014; Mehta et al., 2017). New therapeutic strategies are urgently needed (Rodriguez et al., 2021).

The history of Traditional Chinese Medicine (TCM) in treating diseases is so long as ancient Chinese history, and it has improved the quality of life of the people (Ye et al., 2020). In the present world, human beings worldwide are suffering from COVID-19 (Ye et al., 2021). TCM has made an unparalleled contribution to human beings by resisting this disaster. The use of TCM has played an essential role in reversing the situation of epidemic prevention in China and even the world (Huang et al., 2021). This seems to give us a rare opportunity, and it also reminds us that TCM may play a particular role in the prevention and treatment of AD. Many results demonstrate that TCM, which regulates autophagy, is a potential therapeutic candidate for neurodegenerative disease treatment (Wang Z. Y. et al., 2021), or attenuating Aβ and tau pathology in experimental AD models (Iyaswamy et al., 2020b). It is not surprising that there have been many reports on preventing and treating AD with TCM (Kim et al., 2017; Xu et al., 2021). For example, Yuan-Hu Zhi Tong Prescription mitigates tau pathology. It alleviates memory deficiency in the preclinical models of AD (Iyaswamy et al., 2020a), and a modified formulation of Huanglian-Jie-Du-Tang reduces memory impairments and Aβ plaques in a triple transgenic mouse model of AD (Durairajan et al., 2017).

Coptidis Rhizoma (CR), named Huang Lian, is the dried rhizome of Coptis chinensis Franch., C. deltoidea C. Y. Cheng et Hsiao or C. teeta Wall (Ranunculaceae). It has a significant therapeutic effect on bacillary dysentery, typhoid, tuberculosis, and other diseases (Meng F. C. et al., 2018). Berberine, palmatine, coptisine, epiberberine, jatrorrhizine, and columbine, are the main protoberberine-type alkaloids of CR (Meng F. C. et al., 2018). In recent years, CR has been made new progress in preventing and treating AD, especially its principal feature, berberine, which has become a “star molecule” (Wang et al., 2020; Liang et al., 2021). The role of berberine in the prevention and treatment of AD in antioxidation (Ahmed et al., 2015), anti-inflammation (Cai et al., 2016), and anti-endoplasmic reticulum stress have been reported in many studies (Wu et al., 2021). As we all know, TCM is a complex component system, and the material basis of CR represented by berberine alone missed accord with the holistic concept of TCM. Therefore, we propose using the network pharmacology method to explain CR's overall mechanism in treating AD from the multi-level “component-target-pathway.”

In this study, the blood components of CR were selected as the research object, combined with the data of blood metabolomics and brain transcriptomes. From the view of the component-gene-metabolism level, the mechanism was expounded by utilizing network pharmacology to analyze CR in AD treatment, as shown in Figure 1. This study reveals the various means of TCMs in treating diseases from a new perspective.

In this article, we analyzed the multi-level mechanism of CR in AD treatment. Nineteen components may be the potential active components of CR, and Berberine, Chlorogenic acid, Obacunone, Epiberberine, and Ferulic Acid may be the critical components; in 267 common targets, the potential effective targets are only 69. Four marks are clinically significant among the six key targets: RELA, MAPK8, STAT3, and TGFB1. 3,050 enriched BP terms, 257 enriched MF terms, and 184 enriched CC terms. The BP terms mainly include a response to an inorganic substance, positive regulation of cell death, and cellular response to nitrogen compound; the CC terms mostly have membrane raft, neuronal cell body, and neuron spine; the MF terms mainly involve antioxidant activity, superoxide dismutase activity, oxidoreductase activity. In the MCODE network topology analysis, nine analysis modules were obtained. RELA, TRAF2, STAT3, JUN, and INS were the critical targets of each module.

Various diseases may share the exact mechanism of AD, such as NAFLD, Hepatitis B, Chagas disease, Tuberculosis, etc. Among the significant enrichment pathways, the key pathways were the HIF-1 signaling pathway, the PI3K-Akt signaling pathway, the Toll-like receptor signaling pathway, the NOD-like receptor signaling pathway, and the MAPK signaling pathway. Hypoxia-inducible factor (HIF) regulates protein expression in biological processes, such as neurogenesis, glucose metabolism, erythropoiesis, and angiogenesis (Correia and Moreira, 2010). As we age, the oxygen transport of cells and tissues will be damaged to a certain extent, thus increasing the sensitivity of neurons to injury. Therefore, it is of positive significance to protect the hypoxic adaptability of neurons in aging (Ogunshola and Antoniou, 2009).

Experimental data show that the PI3K-Akt signaling pathway may be an essential target for AD treatment. The PI3K-Akt pathway regulates various biological processes such as cell proliferation, movement, growth, survival, and metabolism and inhibits different neurotoxic mechanisms (Kumar and Bansal, 2022). In addition, the PI3K/Akt signaling pathway depends on the cellular environment. In short, PI3K/Akt is beneficial to activating neurons and neural stem cells, but the activation of microglia may be disadvantageous to the internal environment (Razani et al., 2021).

Neuroinflammation can occur in inflammatory diseases of the central nervous system and may develop into neurodegenerative diseases (Li et al., 2021). The NOD-like receptor is an essential cytoplasmic pattern recognition receptor, which plays a vital role in the host's innate immune response and immune homeostasis (Kong et al., 2017). Systemic inflammation can activate TLR4, NLRP3, inflammatory bodies, and complements in the brain, resulting in neuroinflammation, Aβ accumulation, synaptic loss, and nerve degeneration (Cheng et al., 2014). TNF and TNFR1 are involved in AD-related cerebral nerve inflammation and regulate the formation of Aβ through β-secretase (Yang et al., 2020). Therefore, the potential molecular mechanism of the inflammation-related signaling pathway can be used as a method for the prevention and treatment of AD.

There is evidence that the MAPK signal pathway may be involved in the pathogenesis of AD by regulating the activity of β- and γ-secretase, neuronal apoptosis, and phosphorylation of APP and Tau (Kim and Choi, 2010). AMPK can improve energy metabolism, stimulate autophagy and inhibit inflammation, while HIF-1α can promote angiogenesis and help cells adapt to harsh conditions (Salminen et al., 2016). The recovery/enhancement of autophagy has been considered a method for treating these neurodegenerative protein lesions (Benito-Cuesta et al., 2021).

In the joint analysis of metabolism and pathway, glutathione metabolism, phenylalanine metabolism, nicotinate and nicotinamide metabolism, and arginine biosynthesis were simultaneously enriched. Glutathione (GSH) is the most abundant non-protein mercaptan in cells and an important antioxidant. Compared with healthy older adults, the levels of GSH in the hippocampus of patients with mild cognitive impairment (MCI) and AD are significantly reduced (Liu et al., 2004). The decrease of brain antioxidant GSH is related to oxidative stress (Mandal et al., 2019). Under chronic inflammation, the rise of serum phenylalanine concentration and phenylalanine/tyrosine ratio (Phe/Tyr) may be related to neuropsychiatric symptoms (Wissmann et al., 2013). Immune activation in patients with AD is related to high serum phenylalanine concentration, and the disorder of phenylalanine metabolism in the hippocampus may be an essential mechanism of AD pathology (Liu et al., 2021). L-arginine (L-Arg) is the precursor of nitric oxide and polyamines. It has a variety of functions in human health, such as regulating atherosclerosis, redox stress, inflammation, and the regulation of synaptic plasticity and neurogenesis. It also plays a vital role in age-related degenerative diseases like AD (Asai et al., 2007; Yi et al., 2009).

It is worth noting that berberine can reduce the level of Aβ by altering the hyperphosphorylation of APP in human glioma H4 cells (Yu et al., 2011). In addition, berberine alleviates Tau hyperphosphorylation through PI3K/Akt/Gsk3β pathway (De Oliveira et al., 2016). Some literature has shown that berberine can reduce acetylcholinesterase activity in the cerebral cortex and hippocampus of rats with memory impairment induced by streptozotocin/ethanol, improve memory impairment and maintain essential memory ability (Patil et al., 2015). Improving the function of cholinergic neurons, reducing the abnormal phosphorylation of Tau, and clearing Aβ deposition are the essential mechanisms of CR in AD treatment.

It has been found that berberine can reduce the levels of NF-κB, TLR4, TNF-α, and IL-6 in the brain of adult male cognitive impairment rats induced by lipopolysaccharide and prevent learning and memory impairment (Sadraie et al., 2019). Berberine can also inhibit Aβ-induced neuroinflammation (Jia et al., 2012), block NF-κB signaling, and improve the learning and memory function of APP/PS1 mice (He et al., 2017). The anti-inflammatory of CR may play an essential role in treating AD.

Aβ aggregation can cause excessive oxidative stress in the brain and aggravate neuronal damage, developing into AD-like symptoms (Cheignon et al., 2018). Berberine and jatrorrhizine can achieve neuroprotective effects through antioxidant stress and inhibition of apoptosis (Friedemann et al., 2015; Luo et al., 2017). Ferulic acid (FA) may repair the pathological damage of AD by improving the imbalance of mitochondrial division-fusion kinetics, interfering with oxidative stress and inflammation caused by Aβ aggregation, and then regulating the biological pathways involved in apoptotic programmed cell death (Wang Q. et al., 2019; Wang E. J. et al., 2021). Similarly, chlorogenic acid can control many pathophysiological characteristics of neurodegenerative diseases by improving mitochondrial dysfunction, reducing neuroinflammation and Aβ protein aggregation, and antioxidant stress (Phadke et al., 2021). The improvement of dysfunction, reduction of oxidative stress, and apoptosis may provide a direction for treating AD.

This may be a drug with great potential, as the regulatory effect of plant components of CR on core targets has also been widely reported. We can find detailed data in Table 5. For the IL1B, MAPK8, MMP2, RELA, STAT3, and TGFB1 mentioned in this article. We found that most of the plant components of CR have a down-regulating effect on them, although it is somewhat opposite to the mRNA expression of genes in GEO mentioned in the article, such as MAPK8 decreased significantly in FC and TC. We looked up the literature and found that most of the components were down-regulated to MAPK8, but the overall results were beneficial to our conclusion because the mRNA expression of RELA, STAT3, and TGFB1 increased significantly in AD, and our CR or chemical constituents had a down-regulating effect on them. Therefore, we can speculate that CR can play a role in AD treatment by down-regulating the mRNA expression of IL1B, MMP2, RELA, STAT3, and TGFB1, mediating the HIF-1 signaling pathway, the PI3K-Akt signaling pathway, the Toll-like receptor signaling pathway, and other pathways.

To sum up, the components of CR have multi-target pharmacological effects in AD treatment (Table 6; Figure 11), which helps to bring new insight into the best treatment of AD. This paper studied the multi-component, multi-target, and multi-pathway Mechanism of CR in the prevention and treatment of AD by utilizing a network pharmacology strategy. Berberine is expected to become a potentially effective component in the treatment of AD, which may provide a new direction for the current dilemma of AD treatment. Still, the other therapeutic effects of CR active components on AD have yet to be determined.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

The authors declare that the procedures followed were by the relevant clinical research Ethics Committee's regulations and those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).

X-wY integrated the data and wrote the manuscript. S-qC and L-jX executed the literature search. X-fX and H-lW implemented corrections in the manuscript. X-rL conceptualized and designed the experimental plan. All authors contributed to the article and approved the submitted version.

This study was supported by the National Key Research and Development Program of China (No. 2019YFC1711500) and the National Natural Science Foundation of China (No. 81973480).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.