Role of aerobic glycolysis in alzheimer's disease and research progress of traditional Chinese medicine

LIAO Nai-bin , CHEN Wei , , , ZHU Xiao-min , LIAO Shi-feng , LI Qian-qian , LIANG Yi , MAI Fang-yu , HE Ai-xin

1.Graduate School of Guangxi Univ Tradit Chin Med, Nanning 530001, China

2.Encephalopathy, the First Affiliated Hospital of Guangxi Univ Chinese Medicine, Nanning 530023, China

3.Guangxi Key Laboratory of Basic Research of Tradit Chin Med, Nanning 530001, China

4.Graduate School of Jiangxi Univ Tradit Chin Med, Nanchang 330004, China

Keywords:

ABSTRACT Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a variety of pathogenic factors and complex pathogenesis, so that the disease has a high prevalence and mortality in the world.Although the current diagnosis and treatment equipment and drug research and development keep pace with the times, the current medical technology still can not completely cure the disease, so it is of great significance to explore the pathogenesis and treatment target of AD.The disorder of energy metabolism is one of the characteristic changes in the pathological process of AD.Aerobic glycolysis (AEG) is a special metabolic pathway in the brain, which can rapidly consume glucose to produce energy and substrate for neurons,improve synaptic plasticity, neuroinflammation and oxidative damage, and contribute to the recovery of memory and cognitive function.In recent years, many literatures have reported the mechanism of AEG in AD and the intervention of Tradit Chin Med on this mechanism.The purpose of this paper is to summarize the role of AEG in AD and the related research on the regulation and control of AEG in the treatment of AD by Tradit Chin Med, in order to provide reference and ideas for the prevention and treatment of AD with Tradit Chin Med in the future.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease.At present, the number of AD cases has exceeded 30 million and continues to rise in the world, especially in developing countries including China.Due to the superposition of factors such as an aging population, social pressure and improper lifestyle, it is speculated that the number of AD cases will double in the next 30 years[1].Although a large amount of money has been invested in the drug development and diagnosis and treatment of AD, the current medical methods can only delay the disease of AD but can not cure it completely.It is undeniable that AD is a recognized health problem and health problem in the current society.Therefore, it is particularly important to further study the molecular mechanism of AD in order to identify the pathogenic factors and therapeutic targets, and to explore effective treatment.

Modern medicine believes that its pathological mechanism is complex and interact with each other, including β-amyloid (Aβ)toxic damage, abnormal modification of Tau protein, oxidative stress, neuroinflammation, mitochondrial dysfunction and so on[2].In fact, in the process of inevitable aging, the metabolic network is affected by related signal pathways, proteins and genes, which leads to the gradual down-regulation of aerobic glycolysis (AEG), which can directly or indirectly participate in the pathogenesis of the above-mentioned AD and affect its pathological changes.Therefore,taking AEG as the research target can provide a new idea for the prevention and treatment of AD.

The name of AD disease is not seen in Tradit Chin Med, and it is usually divided into “dementia” and “forgetfulness” categories.Its formation is attributed to senility, long-term illness, internal injury of seven emotions, etc., which leads to the lack of kidney essence,weakness of spleen and stomach, obstruction of qi, and stagnation of phlegm and blood stasis in brain collaterals.With the in-depth study of Tradit Chin Med in recent years, it is reported that Tradit Chin Med has great potential in regulating and controlling AEG and preventing and treating AD.This paper mainly summarizes the role of AEG in AD and the related research on the regulation and control of AEG and AD by Tradit Chin Med, in order to provide some reference for the prevention and treatment of AD with Tradit Chin Med.

1.Aerobic glycolysis

Overview glucose as the main energy source of the human body,glucose produces the energy needed by cells and substrates for biosynthesis through glycolysis, oxidative phosphorylation and pentose phosphate metabolism.In general, glucose can produce a lot of energy by mitochondrial oxidative phosphorylation in an aerobic environment, while glucose can produce lactic acid and a small amount of energy by glycolysis in the cytoplasm under anaerobic or hypoxic conditions.In the 1920s, German scientist Otto Warburg found that the oxygen consumption of tumor cells was lower than that of normal cells, while the levels of glucose metabolism and lactic acid increased significantly.He pointed out for the first time that tumor cells still tend to supply energy for cells through the glycolysis pathway rather than efficient oxidative phosphorylation in an aerobic environment, a phenomenon called the Warburg effect,or AEG.The process is that glucose enters the cell with the help of glucose transporter (GLUTs) and produces a large number of intermediates and lactic acid under the action of key enzymes such as hexokinase (HK), 6-phosphofructokinase (PFK), pyruvate kinase(PK) and lactate dehydrogenase (LDH).Although AEG metabolizes the same glucose as much less energy than mitochondrial oxidative phosphorylation, it can quickly produce substrates and energy needed for cell biosynthesis.

This particular metabolic pattern also exists in the brain and plays different roles in different age groups.During embryonic development, AEG, as the main metabolic mode of the brain,provides the necessary substrate for the proliferation of astrocytes and neural stem cells; in childhood, AEG is mainly involved in the growth of neuronal axons and the formation of myelin; in adulthood,AEG persists in the brain to maintain neuronal vitality and memory function[3].However, in the process of aging, the activity of AEG in the brain gradually decreases, which is involved in the mechanism of neurodegenerative diseases such as AD[4].Promoting AEG activity by regulating related signal pathways, proteins and genes can not only maintain the energy supply of nerve cells, but also regulate brain neurotoxicity, oxidative stress, synaptic energy efficiency,nerve inflammation and other aspects, affecting the occurrence and development of AD.

2.The role of aerobic glycolysis in Alzheimer’s disease

2.1 Aerobic glycolysis inhibits the accumulation and deposition of Aβ neurotoxic

Aβ in the brain to form neuroinflammatory plaques, which is recognized as one of the characteristic pathological manifestations of AD, which can lead to high phosphorylation of Tau protein,decreased energy metabolism, oxidative stress, neuroinflammation and abnormal cholinergic system, which is regarded as the initial factor and central link in the pathogenesis of AD[5,6].It was found that there was a high glucose consumption and an increase in lactic acid levels near the topographic distribution of Aβ deposition in the brain.Using 18 fluorodeoxyglucose positron tomography (18FDGPET), it was observed that there was a close relationship between Aβ and the distribution of AEG in the brain, and in patients with mild cognitive impairment, patients with high amyloid deposition and low AEG activity were more likely to develop towards AD.However, the patients with high AEG activity and low amyloid precipitation were not converted to AD.Neuronal sensitivity to Aβ can be mediated by inhibiting LDH and pyruvate dehydrogenase kinase (PDK) down-regulating the level of AEG[7].It is suggested that Aβ can induce mitochondrial functional defects in AD, which hinders glucose uptake and oxidative phosphorylation, which can drive the compensatory increase of AEG in response to energy deficiency of nerve cells, and high-throughput AEG in the brain can resist the neurotoxicity of Aβ.

2.2 Aerobic glycolysis alleviates oxidative stress

The oxygen consumption of the brain accounts for about 1/5 of the total oxygen consumption, and there are a large number of active oxidation clusters (ROS).Aging, mitochondrial damage and AD pathological product accumulation and other factors weaken the antioxidant capacity of brain tissue, resulting in oxidative stress.It runs through all stages of the course of AD and increases with the deterioration of the disease.AEG, which is independent of mitochondria and limits the level of oxidative phosphorylation,can reduce mitochondrial ROS and membrane potential, which has neuroprotective effect.Studies have shown that increasing the level of key enzymes in glycolysis can up-regulate the AEG flux to promote the formation of intermediate glucose-6-phosphate, which enters the pentose phosphate pathway under the action of glucose-6-phosphate dehydrogenase, promotes the level of NADPH to maintain the reduced state of antioxidant glutathione, and reduces the oxidative damage of neurons caused by ROS and peroxide[8].In AD astrocytes, the level of AEG can be up-regulated by activating PI3K/Akt signal pathway, which can not only alleviate oxidative stress, but also promote the growth of axons and dendrites, which is helpful for astrocytes to support neurons[9].

2.3 Aerobic glycolysis to improve synaptic plasticity

Synaptic plasticity means that the morphology and function of synapses can maintain their vitality for a long time, which is the biological basis for maintaining the ability of learning and memory.In the pathological process of AD, the gradual deterioration of synaptic plasticity leads to the continuous decrease of learning and memory storage ability, which is the key link of AD.It has been found that AEG is involved in the repair of synaptic plasticity defects, and one of the main roles of high-throughput AEG in astrocytes is to maintain a high level of intermediates, in which glycerophosphate 3-phosphate can form L-serine through oxidative phosphorylation, which can shuttle to neurons and convert into D-serine, which is a highly efficient coagonist of synaptic N-methyl-D-aspartic acid (NMDA) receptors.Promote synaptic efficiency enhancement and cognitive function recovery.At the same time,lactic acid, the final product of AEG, can be transported to neurons through the lactic acid shuttle pathway to act as key signal molecules or energy substances to regulate neuronal synaptic plasticity[10,11].However, the overexpression of circadian rhythm-related proteins Clock and Bmall1 in AD astrocytes inhibits the levels of HK1 and LDHA, which is not conducive to the AEG process and lactic acid production, and can decrease synaptic plasticity and aggravate the pathological changes of AD[12].

2.4 Aerobic glycolysis regulates neuroinflammation

Neuroinflammation means that the central nervous system recognizes various infections or injuries and then mediates the immune response.The persistent Aβ deposition and abnormal Tau protein in AD always stimulate the activation of neuroinflammation and affect the pathological trend of AD.It has been found that AEG is closely related to the neuroinflammatory response of AD.On the one hand, high-throughput AEG can activate AKT signal pathway,increase GLUTs level, promote glucose uptake, and maintain the energy supply of microglia.On the other hand, AEG can activate EphA2/p38MAPK and mTOR/HIF1 α signaling pathways to promote microglia to release pro-inflammatory cytokines and phagocytosis of harmful substances and impaired and dead cells,which is helpful to initiate and implement adaptive immunity and has neuroprotective effect.However, using 2-deoxy-D-glucose or knock-down glycolysis key enzyme HK2 to inhibit microglia AEG could significantly down-regulate the gene and protein expression levels of IL-1β and TNF-α[13,14].

3.Aerobic glycolysis regulated by Tradit Chin Med in the treatment of Alzheimer’s disease

3.1 Tradit Chin Med Compound

3.1.1 Liuwei Dihuang decoction

Liuwei Dihuang decoction is recorded in Qian Yi, which has the effect of tonifying kidney and nourishing yin and nourishing brain.Clinical observation found that Liuwei Dihuang Pill can significantly improve the cognitive ability and syndrome efficacy of patients.After years of pharmacological research on Liuwei Dihuang decoction, the Academy of military Medical Sciences extracted its main active components to create Liuwei Dihuang glycosides.Zhang H C[15] found that using rapidly aging mice as AD model mice,Liuwei Dihuang glycosides can not only increase the expression level of GLUT1 and GLUT3, promote glucose uptake, increase glucose AEG flux, but also increase the activity and expression of glycolysis key enzymes HK and PDH.Further increase the level of AEG, improve the energy metabolism of brain and the learning and memory ability of AD mice.

3.1.2 Dihuang Yinzi

Dihuang Yinzi is recorded in the Cold and Cool School Liu Wansu,which has the effect of tonifying kidney and filling marrow, tonifying yin and yang, opening orifices and resolving phlegm.Clinically, this prescription or chemical prescription is often used in the treatment of senile dementia and has definite clinical effect.A clinical observation data showed that the patients with AD treated with conventional western medicine plus Dihuang Yin decoction were significantly better than those in the routine treatment group in terms of cognitive function and memory ability[16].Studies have shown that Dihuang Yinzi not only has the effects of anti-inflammation, anti-oxidation and anti-apoptosis in AD, but also can protect neuron-astrocyte lactic acid shuttle system and abnormal energy metabolism[17,18].Yu H N[19] found that after intragastric administration of Rehmannia glutinosa in APP/PS1 mice once a day for 150 d, it could significantly up-regulate the phosphorylation level of PI3K and Akt in brain astrocytes and the expression of downstream glycolysis key enzymes PFK-1 and ALDH3B2, improve the AEG activity of astrocytes, promote energy metabolism in the brain, and correct the structural and functioal abnormalities of astrocytes.

3.1.3 Shenzhiling Oral liquid

Shenzhiling Oral liquid was prepared by Professor Lin Shuisen on the basis of the theory of “heart governing the mind” and his own long-term clinical experience in treating AD.Its components are Codonopsis pilosula, cassia twig, Poria, keel, oyster, Acorus tatarinowii and Yuanzhi, and has the effects of relieving heartyang, tonifying heart-qi and resolving phlegm.Clinical observation showed that Shenzhiling oral liquid could effectively improve the cognitive function impairment and mental behavior abnormality of patients with early AD[20].Experimental studies have confirmed that it can promote glucose uptake and AEG activity by activating PI3K/Akt/mTOR and AMPK signal pathways, thus improve glucose metabolism, regulate the expression of synaptic and myelin-related proteins, improve synaptic plasticity and neuronal ultrastructure, and play a neuroprotective role in AD[21].

3.1.4 Compound preparation of Radix Astragali and Breviscapine

Compound preparation of Radix Astragali and Breviscapine has the effect of tonifying qi, invigorating blood circulation and dredging collaterals, and is often used in clinical treatment of AD internal neurodegenerative diseases.Miao J C[22] found that in the AD rat model established by aluminum chloride and D-galactose, the compound preparation of astragalus and breviscapine could increase LDH, promote the production of lactic acid, the final product of AEG, and up-regulate the level of superoxide dismutase and downregulate the level of malondialdehyde.It is suggested that the compound preparation can promote the process of AEG and inhibit oxidative stress, which can improve the cognitive and memory function of AD.

3.2 Single Tradit Chin Med and its active ingredients

3.2.1 Epimedium

Epimedium is a Tradit Chin Med into the two meridians of the liver and kidney, which has the effect of tonifying the kidney and helping yang, strengthening muscles and bones, and may have great potential for the prevention and treatment of AD.Icariin, as its main active ingredient, has been proved to significantly increase the activities of GLUT1, GLUT2 and GLUT3 in the hippocampus of AD mice competing with HK, PFK and HK by activating non-classical Wnt signal pathway, improve the abnormal metabolism of AEG and oxidative phosphorylation pathway in the brain, save the lack of brain energy metabolism, and inhibit the accumulation of Aβ and abnormal phosphorylation of Tau protein[23,24].

3.2.2 Andrographis paniculata

Andrographolide is an effective component of andrographis paniculata, which belongs to diterpene lactones.Modern pharmacological studies have confirmed that it has biological activities such as regulating immunity, anti-oxidation, protecting nervous system and so on in the prevention and treatment of AD.Moreover, andrographolide, as an agonist of classical Wnt signal,can activate Wnt/ β-catenin signal pathway, on the one hand, it can enhance the activity of AMPK and mediate the up-regulation of GLUT3 and GLUT4 levels in neurons, and promote glucose uptake; on the other hand, it can increase the activity of key enzymes of AEG by activating PI3K/Akt/mTOR signal pathway, which is helpful to glucose metabolism in cerebral cortex and hippocampus.In addition, long-term use of andrographolide can also increase the flux of pentose phosphate pathway, increase the level of NADPH,and enhance the antioxidant effect[25,26].

3.2.3 Chinese yam

Chinese yam, is one of the four major Huaiyao, with anti-AD, antiaging, enhance resistance and other effects.The active component DM-1 extracted from it has been proved to significantly up-regulate the content of PDH in the hippocampus of AD mice, suggesting that DM-1 may regulate the disorder of energy metabolism and improve the cognitive impairment of AD by promoting the level of AEG[27].

3.2.4 Uncaria

Rhynchophylline is one of the effective components of Uncaria,which can resist Aβ toxicity, glutamate excitotoxicity and neuroinflammation in AD, and improve synaptic dysfunction,neuronal loss and cholinergic nervous system damage[28].In vitro experiments confirmed that rhynchophylline can increase LDH level and AEG rate, improve cell metabolic activity, and increase the flux of pentose phosphate pathway has a strong antioxidant effect[29].

3.2.5 Chili pepper

Capsaicin is a pungent compound in capsicum and an agonist of vanillic acid subtype 1(TRPV1) at transient receptor potential.It can reduce the level of A β production and Tau protein phosphorylation,enhance synaptic function, and play an important role in the repair of learning and memory ability of AD mice.Moreover, capsaicinmediated TRPV1 activation is an important target for microglia metabolic reprogramming.It promotes microglia AEG and enhances microglia phagocytosis by activating mTOR/Akt/HIF-1α signaling pathway[30].

3.3 Acupuncture therapy

Acupuncture therapy is a major feature of prevention and treatment of diseases in Tradit Chin Med.Clinical treatment of AD follows the principles of dredging the governor and tonifying the brain,tonifying the kidney and wisdom, and is often treated according to syndrome differentiation from the aspects of governor vessel,kidney, brain and so on.Baihui, Sishen Cong, Shenting, Yintang,Shuigou, Yongquan and other acupoints are usually selected, and the clinical effect is significant[31].Experimental studies have also confirmed that acupuncture can reduce the pathological products of AD, inhibit oxidative stress, neuroinflammation, cholinergic activity,improve synaptic plasticity, and achieve the purpose of treating AD.Zhang B X[32] found that electroacupuncture at Baihui and Shenting of APP/PS1 mice could improve the cerebral glucose metabolism and improve the learning and memory ability of AD mice.The mechanism may be that the activation of AMPK promotes the expression of PFKFB3, HK2 and PKM2 in the hippocampus, thus increasing the activity of AEG.

4.Summary

With the deepening of the aging of the population, chronic diseases including AD and geriatric diseases are becoming more and more prominent.As the pathogenesis of AD is extremely complex, the prevalence and mortality of AD patients are increasing year by year.AEG is one of the pathways of glucose metabolism, which participates in brain energy supply and cell biosynthesis.It plays an important role in AD by regulating Aβ neurotoxicity, oxidative stress, neuroinflammation and synaptic plasticity.

Tradit Chin Med is a valuable experience accumulated by our ancestors in the struggle with diseases for thousands of years.It has strong traditional color and cultural heritage, and has distinct characteristics and advantages in the prevention and treatment of AD.Focusing on glucose AEG pathway, Tradit Chin Med can increase the expression of GLUTs, key enzyme genes and proteins, activate Akt, Wnt and AMPK signal pathways, promote the expression of AEG in the brain, improve the pathological manifestation and learning and memory ability of AD, and have neuroprotective effect.It is hoped that there will be a more comprehensive, in-depth and systematic study on the intervention of Tradit Chin Med on brain energy metabolism in the treatment of AD in the future, so as to provide more sufficient basis and clinical ideas for the treatment of AD with Tradit Chin Med.