Alzheimer's disease (AD) has become the third most disabling and fatal disease in the elderly after cardiovascular and cerebrovascular diseases and malignant tumors, and with the increase of age, the risk of disease is significantly increased. Its clinical manifestations mainly include partial or comprehensive impairment of thinking, memory, judgment, behavior, language and other abilities. At present, the global incidence is 2% - 3% and that in China is 1% - 2%. With the aggravation of China's aging population, its prevalence is rising, and the resulting medical and economic burden is also gradually increasing [1-2]. According to the statistics of ad international organization, it is estimated that the number of dementia patients worldwide will reach 152million by 2050, of which 60% - 70% will be AD patients [3].
. At present, the drugs used in the clinical treatment of ad mainly include cholinesterase inhibitors, glutamate receptor antagonists, antipsychotics, calcium channel blockers, serotonin reuptake inhibitors, etc., but the curative effect is poor [4]. Some data show that the occurrence and development of AD are related to many factors such as environment, genetics, self metabolism and so on, and the pathogenesis of ad is still unclear. Therefore, effective control and treatment of it has become an urgent problem to be solved.
Astragalus membranaceus is a leguminous plant Astragalus mongholicusAstragalus membranaceus (Fisch.) Bge. var. mongholicus(bge.) Hsiao or Astragalus membranaceusA. membranaceus The dry root of (fisch.) bge. has a sweet taste and mild temperature. It has the effects of Invigorating Qi and Yang, fixing the surface and stopping perspiration, promoting water and reducing swelling [5], and is listed as the top grade in the Shennong materia medica classic. Saponins, flavonoids and polysaccharides, as the main effective components of Astragalus membranaceus, jointly exert anti-inflammatory, antiviral, antioxidant, immune regulation, cardiovascular and nervous system protection, anticancer, antitumor and other pharmacological effects [6]. Astragalus membranaceus is a high-frequency drug for the treatment of ad [7].The drug is used in the treatment of AD.The drug is mainly used in the treatment of AD.The drug is used in the treatment of AD.The drug is mainly used in. In recent years, researchers have gradually paid attention to the protective effect of Astragalus membranaceus and its active ingredients on the nervous system. It was found that it can produce multifaceted therapeutic effects on ad [8]. This article reviews the research progress of the mechanism of Astragalus membranaceus and its active ingredients in the treatment of ad in recent years, so as to provide a basis for the development and utilization of Astragalus membranaceus medicinal resources and its active ingredients, and provide a reference for the treatment of ad with traditional Chinese medicine.
1 improve learning and memory ability
. In addition, 70% - 90% of AD patients will have hallucinations and identity recognition disorders. After AD onset and no treatment for 2-4 years, they often have psychotic symptoms such as delusions, which seriously affect the normal life of patients and their families [9]. There are many kinds of experimental animal models and modeling methods used in AD drug screening, including rats, mice, fruit flies, zebrafish, nematodes, etc. Researchers usually use water maze test, life test, climbing ability test to evaluate the behavior and learning and memory ability of experimental animals before and after drug intervention.
Wuyuepeng et al. [10] used astragaloside IV to intervene scopolamine induced learning and memory impairment mice, and found that astragaloside IV could significantly improve their learning and memory behavior, and its treatment mechanism may be through increasing the activity of total superoxide dismutase and reducing the production and expression of malondialdehyde (an important peroxidation product reflecting the oxidative stress condition) in brain tissue. Huang et al [11] found that astragaloside IV could improve the learning and memory ability of ad male rats by reducing the expression of β - amyloid precursor protein (APP), β - secretase and β - amyloid protein 1-40 (a β 1-40) in hippocampal tissue, thereby improving its antioxidant and immune regulatory effects, and playing the effect of delaying aging.
Yaohui et al [12] used open field and water maze tests to confirm that Astragalus polysaccharide can improve the learning and memory ability of aged rats, and found that the decreased learning and memory ability of rats may be related to the abnormal expression of neuroplasticity related proteins in the hippocampus. Studies have shown that Astragalus polysaccharide can improve the learning and memory function and hippocampal neuronal morphology of AD mice induced by a β 1-42, specifically by improving blood-brain barrier permeability and inhibiting the protein levels of a β and interleukin-6 (IL-6) to play a therapeutic role in AD [13].
Li et al [14] found that Astragalus Polysaccharide 1 mg/ml can significantly improve the climbing ability of a β 42 transgenic flies, and when the mass concentration increases to 3 mg/ml, it can significantly extend their life span. However, using the same concentration of Astragalus polysaccharide totau. Oral administration of Astragalus granule can improve the learning and memory ability of AD rats induced by a β 25-35, and its mechanism may be through reducing the content of matrix metalloproteinase 9 (MMP9) in brain tissue, preventing the structure of tight junction protein occludin from being destroyed, so as to maintain the structure and function of blood-brain barrier and improve AD symptoms [15].
. Another study reported that fermented Astragalus membranaceus could effectively improve the learning and memory ability of natural aging model rats, and improve the antioxidant indexes in serum and brain of rats, indicating that fermented Astragalus membranaceus may play a brain protective role by improving its antioxidant capacity [17]. Liu et al [18] used molecular docking technology to simulate the binding sites of active ingredients in Astragalus membranaceus with 5-ester oxygenase and acetylcholinesterase, and found that they were well combined with potential targets of active ingredients such as calycosin, calycosin-7-glucoside, 3-hydroxy 9,10-dimethoxyerythrobase, suggesting that the above ingredients also have potential therapeutic effects on AD.
2 inhibits a β production and aggregation
The amyloid cascade theory is one of the widely accepted pathogenesis of AD. A β is the main component of senile plaques and an important sign of AD. A large number of studies have shown that a β can induce apoptosis and necrosis, indicating that a β is one of the main causes of cognitive dysfunction and death. . The accumulation of this protein can lead to neuronal toxicity, interfere with the functions of cholinergic, serotonergic, norepinephrine and dopamine neurons, and promote the occurrence of ad [20].
Astragaloside Ⅳ (2 mg/kg) can significantly reduce the content of a β 1-40 and a β 1-42 in the brain of app/ presenilin 1 (PS1) transgenic mice. Its mechanism of action is that astragaloside Ⅳ activates wnt/ β -catenin signaling pathway, downregulates the expression of PS1, PS2, nicastrin (NCT) and amyloid precursor protein cleaving enzyme 1 (BACE1) and other app lyases, thus preventing the decomposition of app to form a β precipitation, playing a role in delaying or treating AD [21].The.
, The expression of inflammatory proteins such as NLRP3) and cleaved caspase-1 (caspase-1) and the content of inflammatory factors such as IL-1 β, tumor necrosis factor - α (tnf- α), IL-6 could inhibit the transformation of app to a β precipitation in the brain of model rats.
. As-iv treatment of app/ps1 mice can increase PPAR γ expression, inhibit BACE1 activity, reduce neuritic plaque formation and reduce a β levels.
In addition, studies have found that GW9662, a PPAR γ antagonist, has inhibitory effects on the above beneficial effects [24]. Feihongxin et al [13] found through research that Astragalus polysaccharide could significantly reduce the levels of a β and IL-6 in the hippocampus of AD mice, significantly increase the expression of nuclear factor E2 derived 2-like 2 (Nrf2) in the nucleus of app/ps1 mice, reduce its expression in the cytoplasm, and restore the expression levels of kelch like ECH associated protein 1 (Keap1), reactive oxygen species, glutathione peroxidase (GSH PX) and malondialdehyde. Showed that Astragalus Polysaccharide might alleviate cognitive impairment and a β accumulation in app/ps1 mice through Nrf2 pathway [25].
Astragalus polysaccharide may inhibit the positive expression of glycogen synthase kinase-3 β (GSK-3 β) in the hippocampus of AD rats induced by a β 25-35 through activating wnsignaling pathway, resulting in the reduction of β -catenin degradation, thereby inhibiting the deposition of a β [26]. Songyajuan et al [27] found that oral administration of Astragalus granule can improve AD symptoms by increasing the content of P-glycoprotein and low density lipoprotein receptor related protein 1 (LRP1) in the blood-brain barrier of AD rats induced by a β 25-35, promoting the transport of a β outside the brain, thereby reducing its deposition in the brain. Another study showed that Astragalus Polysaccharide alone had the same intervention effect on lpr1 [28]. .
3 inhibit nerve cell injury or apoptosis
Mitochondrial dysfunction caused by a β plays an important role in the pathogenesis of AD. A large number of studies have shown that the opening of mitochondrial permeability transition pore (MPTP) is involved in a β - induced neuronal death and reactive oxygen species production. A β can inhibit the expression of PPAR γ and brain-derived neurotrophic factor (BDNF) in hippocampal neurons, and inhibit tyrosine kinase receptor B (TrkB) phosphorylation, which may lead to cortical neuron degeneration and neuronal apoptosis by inducing bdnf/trkb/p-protein kinase B (Akt) / p-gsk-3 β / β -catenin signal transduction defects and mitochondrial dysfunction [30].
Wang et al [31] found that as-iv may promote the expression of PPAR γ, regulate the transcription level of BDNF and increase its expression, activate the bdnf/trkbsignaling pathway, inhibit hippocampal neuronal injury and death in model mice, and ultimately improve cognitive dysfunction. Exogenous BDNF can protect neurotoxicity and apoptosis caused by a β, while as-iv cannot exert neuroprotective effect when PPAR γ is inhibited.
Astragaloside Ⅳ may improve a β - induced memory impairment and hippocampal neuronal apoptosis by promoting PPAR γ activation, inhibiting the expression of BDNF, strengthening the PPAR γ /bdnfsignaling pathway. . In vitro studies also confirmed that astragaloside IV could reverse a β - induced cytotoxicity, apoptosis, mitochondrial distress and synaptic toxicity, and reduce the expression of p-trkb, p-Akt, p-gsk-3 β and β -catenin in rat cortical neurons [30].
Endoplasmic reticulum stress (ERs) is also one of the important causes of promoting programmed cell death in the early stage of AD. Ma et al. [32] took rat adrenal pheochromocytoma PC12 cells induced by a β 25-35 as the research object, and found that astragaloside IV has a protective effect on it. The mechanism is that astragaloside IV inhibits the expression of p38 mitogen activated protein kinases (MAPK) - related proteins and its signaling pathway by reducing the level of intracellular reactive oxygen species, thereby inhibiting the level of ers in model cells and reducing programmed cell death during ad.
Chang et al [33] showed that astragaloside IV could inhibit apoptosis induced by a β 25-35, and inhibit the increased expression of Caspase-3, increased DNA fragmentation and hyperphosphorylation of tau protein. . A β can activate glial cells and cause neuronal cell death by increasing the expression level of inducible nitric oxide synthase (iNOS) and nitric oxide content in the cytoplasm [35-36].
. The results of Jia Ning et al [38] showed that Astragalus polysaccharide could improve the spatial memory ability of app/ps1 transgenic mice, and its mechanism might be through the upregulation of B-cell lymphoma-2,Bcl-2）.
Several other studies have shown that [39-40], Astragalus granule and astragalus extract can inhibit the pro apoptotic protein Bcl-2-related X protein in the hippocampus of AD model rats, and increase the expression level of anti apoptotic protein bcl-2. And after astragalus extract intervened in AD model rats, the expression levels of cyclooxygenase-2 (COX-2) and iNOS in hippocampal tissue were significantly decreased, and showed a dose correlation [41].
4 inhibition of neuroinflammation
Microglia, an immune cell closely related to neuroinflammation, can play different roles in promoting the disease in different stages of ad [42]. ; However, in the environment of high concentration of a β, microglia are overactivated and produce toxic effects on neurons by releasing a large number of neuroinflammatory factors [43].
Studies have shown that astragaloside IV 20-80 mg/kg can significantly improve the learning and memory function of lipopolysaccharide induced AD model mice, and astragaloside IV can reduce the release of inflammatory factors such as IL-1 β, tnf- α, IL-6, nitric oxide in the hippocampus by inhibiting the excessive activation of microglia, so as to achieve the therapeutic effect on ad [44]. Studies have shown that astragaloside IV can inhibit the activity of microglia, reduce the levels of IL-1 β and tnf- α, inhibit neuroinflammatory response based on the mitogen activated protein kinase 5 (MEK5) / extracellular signal regulated kinase 5 (ERK5) signaling pathway, and also protect brain function by reducing the expression levels of glucose regulated protein 78 and CCAAT enhancer binding protein homologous protein [45].
Zhaoqiyue et al [46] found that astragaloside IV could significantly reduce the level of oxidative stress in lipopolysaccharide induced AD model mice, and astragaloside IV administration could down regulate the protein expression of gp91phox and p22phox, the two most important cellular subunits of reduced coenzyme II (NADPH) oxidase, and reduce the content of reactive oxygen species and malondialdehyde in the brain of mice, playing a role in the treatment of AD.
Chen et al [47] used as-iv to intervene in a β - induced AD mouse model, and the results showed that as-iv could inhibit neuroinflammation in model mice by inhibiting microglia activation and neuronal damage, downregulating NADPH oxidase. Astragaloside Ⅳ can significantly reduce the cognitive function of AD mice, and its mechanism may be that astragaloside Ⅳ inhibits the protein expression of nf- κ B inhibitory protein and phosphorylated nf- κ B p65 in cells and lipopolysaccharide induced BV-2 cells in mouse brain microgliaIL-1β、COX-2、iNOSandTNF-α MRNA expression, and inhibit the entry of phosphorylated p65 into the nucleus [48]. Astragaloside IV can play a therapeutic role in AD from many aspects, and its specific anti ad mechanism is shown in Figure 1.
5 conclusion and Prospect
The pathogenesis of AD has not been completely clear (there have been many hypotheses about the etiology of AD, including a β toxicity hypothesis, tau protein hypothesis and other hypotheses [49-50]), leading to some limitations in drug screening ideas, which may also be the potential reason for the lack of new anti ad drugs in recent years. With the gradual application of multi omics technology in AD mechanism research and drug screening, the use of systems biology methods to further explore the pathogenesis of ad or drug screening is expected to provide new ideas for the development of new drugs for AD. Therefore, the research idea of treating AD from single target to multi-target, from single drug to compound may be the key to uncover the pathogenesis and Prevention Countermeasures of ad [51-52].
. Studies have shown that the mixed intervention of aspirin 30 mg/kg and Astragalus granule 3 mg/kg has a significant effect on the learning and memory ability of AD rats, and its mechanism may be related to the inhibition of inflammatory factors such as IL-6 and tnf- α [53]. Studies have shown that the effective component compound composed of icariin astragaloside IV puerarin at a ratio of 3 ∶ 2 ∶ 2 was used to intervene appswe/ ps1de9 double transgenic mice and mouse hippocampal neuron HT22 cells. The results showed that it could effectively improve the learning and memory ability of mice, and its mechanism might be to up regulate the expression of hepcidin, promote the expression of key enzymes for app hydrolysis, inhibit the formation of BACE1, thereby reducing the generation of a β and achieving the therapeutic effect on ad [54-55]. Sang Xingchen [56] found that Astragalus membranaceus + Pueraria lobata had the best prevention and treatment effect on ad in the comparative study of the effects of different disassembled prescription groups of Astragalus membranaceus powder, and its prevention and treatment effect was related to the inhibition of the activation of microglia and astrocytes.
Another study showed that Huangqi Sanxian decoction could reduce glial cells in the hippocampus of AD rats caused by a β 1-40 [57]. Zhaohong et al [58] combined Astragalus, Lily and Hippophae rhamnoides, and through network pharmacology prediction and experimental verification, found that its improving effect on learning and memory ability of mice was related to inhibiting the expression of inflammatory factors in the hippocampus and alleviating inflammatory injury. .
In conclusion, Astragalus membranaceus and its active ingredients can improve learning and memory ability, and exert ad protective effects by inhibiting a β production and aggregation, inhibiting nerve cell injury or apoptosis, and inhibiting neuroinflammation. In addition, studies have confirmed that Astragalus membranaceus and its active components can also improve AD symptoms by regulating oxidative stress [25]. Astragalus membranaceus has the effects of anti-oxidation, anti-aging, anti-virus, improving immunity, protecting cardiovascular and cerebrovascular systems, etc. the natural extract of Astragalus membranaceus has been used in clinical treatment of circulatory system, respiratory system, endocrine system and other related diseases [60-62]. However, at present, the research on the mechanism of Astragalus membranaceus and its active ingredients against ad still stays in the cell or animal experiments in vitro. Although Astragalus membranaceus is often used to intervene AD patients in clinic, it only stays in the efficacy evaluation and lacks deeper mechanism research, which greatly hinders the further application of Astragalus membranaceus in the prevention and treatment of AD and is worthy of further exploration.
Source: Wang Zhe, Ma DingCai, Wang Maomao, Liu Ting, Gao Feiyun, Zhang zhuanhong, Wang Yanjun, Zhang Yugui, Li Yuefeng. Research progress on the mechanism of Astragalus membranaceus and its active ingredients in the prevention and treatment of Alzheimer's disease [j]. Chinese herbal medicine, 2024, 55 (6): 2094-2100
Related components of Astragalus membranaceus:
Bp0211 astragaloside II astragaloside II 84676-89-1
Bp0434 cycloastragalol 78, 574-94-4
Bp0213 astragaloside IV 84687-43-4
Bp0210 astragaloside I 84680-75-1
Bp1711 astraisoflavan-7-o - β - D-glucoside 136087-29-1
Bp0212 astragaloside III astragaloside III 84687-42-3
Bp1719 isoastragaloside I 84676-88-0
Bp0062 Astragalus 3-hydroxy-9,10-dimethoxypterocarpan 73340-41-7
Bp2179 cycloastragalol-6-o - β - D-glucoside 86764-12-7
Bp1630 isoastragaloside II 86764-11-6
Bp3917 isoastragaloside IV 136033-55-1
Bp0435 cyclogalegenin 84605-18-5
Bp3905 neoastragaloside I 1324005-51-7
Bp3919 4 β - hydroxyastragaloside astraganoside 1011711-05-9
Bp5094 safflower rock Astragalus membranaceus coumestrol b Hedysarimcoumestan B 899436-04-5
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