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Traditional Chinese Medicine: Role in Reducing β-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The major characteristics of AD are amyloid β plaques, apoptosis, autophagy dysfunction, neuroinflammation, oxidative stress, and mitochondrial dysfunction. These are mostly used as the significant indicators for selecting the effects of potential drugs. It is imperative to explain AD pathogenesis and realize productive treatments. Although the currently used chemical drugs for clinical applications of AD are effective in managing the symptoms, they are inadequate to achieve anticipated preventive or therapeutic outcomes. There are new strategies for treating AD. Traditional Chinese Medicine (TCM) has accumulated thousands of years of experience in treating dementia. Nowadays, numerous modern pharmacological studies have verified the efficacy of many bioactive ingredients isolated from TCM for AD treatment. In this review, representative TCM for the treatment of AD are discussed, and among these herbal medicines, the Lamiaceae family accounts for the highest proportion. It is concluded that monomers and extracts from TCM have potential therapeutic effect for AD treatment.


INTRODUCTION
Alzheimer's disease (AD) is the most common neurodegenerative disease with high mortality in adults (Van Cauwenberghe et al., 2016;El Kadmiri et al., 2018). The prevalence of AD has been increasing, and age is considered the major risk factor (Alzheimer's Association, 2018). Current studies show that, globally, 44 million people live with dementia. Moreover, that number is expected to triple by 2050 as the population ages and the AD onset tends to be younger ages (Lane et al., 2018). The symptoms of AD include cognitive impairments, memory loss, and executive function loss, hence a hefty burden to the society (Alzheimer's Association, 2018). The pathogenesis of AD is characterized by b-amyloid plaques deposition, tau protein hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, autophagy dysfunction, and oxidative stress (Choi, 1995). The main cause of AD is mutation in either of these three genes-amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) gene. The symptoms of fAD generally occur earlier than sporadic AD between the age of 30 and 50 years (Bateman et al., 2011). A key component of extracellular senile plaque is amyloid b peptide (Ab). Amyloid plaques are Ab with 40 or 42 amino acids (Ab40 and Ab42) that cluster abnormally extracellularly. The two metabolites are produced by APP after b-secretase and gsecretase cleavage (Fleisher et al., 2008;Fan et al., 2017). Once APP levels are abnormal, Ab accumulates causing tau phosphorylation and aggregation to form neurofibrillary tangles (NFTs). NFTs are insoluble twisted fibers made up of clustered hyperphosphorylated tau proteins in AD neurons. Normally, tau pathology begins at the medial temporal lobe allocortex and then spreads to the united neocortex (Lindwall and Cole, 1984;Serrano-Pozo et al., 2011). The Ab and tau pathology build up causes endoplasmic reticulum stress (ER stress), leading to synaptic dysfunction and AD neurodegeneration (Richardson et al., 2015) (Figure 1). Besides, a recent study revealed that Ab and reduced glutamate reuptake levels can trigger hyperexcitation in sensitive neurons. Inactive neurons are resistant to Abmediated hyperactivation, whereas hyperactivity occurs in active neurons. This hyperactivation vicious cycle can be maintained by Ab-induced AD brain extracts and Ab-dimers (Zott et al., 2019).
The current approved drugs for the clinical treatment of AD are cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid (NMDA) receptor antagonists (Sun et al., 2012). Donepezil, rivastigmine, galantamine, and memantine are usually used to treat AD, but these drugs are all single-target drugs. However, they display modest and transitory symptoms improvement accompanied by side effects and hardly prevents or reverses the disease (Silva et al., 2014). Therefore, it is necessary to find better drugs for AD treatment.
Traditional Chinese medicine (TCM) has been established in China health care system over thousands of years (Tang et al., 2008;Xu and Yang, 2009). It has played a very important role in the treatment of chronic diseases such as lung cancer, coronary heart diseases, allergy, diabetes, and infections (Li and Brown, 2009;Gu et al., 2010;Shi et al., 2012;Guo et al., 2012;Liu et al., 2014;Jiang et al., 2016;Zhu et al., 2017). TCM is usually viewed as more accessible, affordable, and acceptable form of treatment, and nearly a quarter of all modern drugs are derived from natural products. Thus, TCM is the basis of primary health care system and innovative medicines (Chan et al., 2014). TCM has been frequently applied in the treatment of dementia and has shown exceptional advantages due to its multi-target, multisystem, multi-link, and multi-pathway capacity. There are numerous prescriptions for treating dementia in the historical records (Luo et al., 2014), such as; Kaixin Powder, Naoling Decoction, Puzzle decoction, Huannaoyicong Decoction, and Compound Formula Rehmannia that have a significantly improve intelligence, anti-fatigue, enhance immunity, delay senility, improve memory, prevent, and treat dementia without noticeable side effects (Zang et al., 2016). Recently, some scholars conducted a general analysis on twenty eligible studies with 1,767 subjects in eight database searches. These studies investigated the combined use or compared application of TCM and clinical drugs, such as donepezil. They found out that TCM as adjuvant therapy exhibited an additive anti-AD advantage and was mainly safe and well tolerated in AD patients. These properties are not in the present approved drugs . According to reported evidences focus on treating AD is more on early detection of the pre-symptomatic phase and the prevalence of early dementia signs. However, TCM has wealthy clinical impact and experience in the prevention and management of chronic diseases including AD. Therefore, there is need to focus on the therapeutic potential of TCM for AD treatment (Hügel, 2015). Active compounds extracted from TCM have therapeutic effects on AD in vivo and in vitro, and some TCM drugs have been applied in clinical trials, providing an approach for AD drug development. Modern pharmacological researches confirmed that bioactive compounds extracted from TCM such as morroniside, curcumin, triptolide, and berberine (Ber) have anti-AD activity (Gu et al., 2004;Fan et al., 2017;Huang et al., 2017;Chen et al., 2018b). Thus, TCM is a potential source of AD drug. Therefore, it is important to analyze and summarize the research status of TCM as anti-AD drug.
In this review, we show TCM's active components obvious effect on AD. These components are: monomers, such as safflower yellow (SY), crocin, b-asarone, matrine, linalool, icariin, and extracts like Dracoephalum moldavica L. flavonoid, Dendrobium nobile Lindl. alkaloids, Achyranthes bidentata Blume, and Coptis chinensis Franch. watery extract. It is shown that among these TCM that have therapeutic potential for AD, the Lamiaceae family accounts for the highest proportion, and for monomer components, the flavonoids, alkaloids, and polyphenols have significant activity in treating AD. We summarize these in prevention and treatment of AD by reducing Ab production, apoptosis, autophagy, neuroinflammation, oxidative stress, and mitochondrial dysfunction.

AD TREATMENT ACCORDING TO PATHOLOGICAL PROCESSES
According to AD pathogenesis, the effective therapeutic effects of TCM's monomers and extracts generally exert their effects in the following ways ( Figure 2).

b-Amyloid Production Reduction
Ab plays a crucial role in AD pathogenesis, and neurotoxicity induced by Ab is the chief cause of AD (Hung and Fu, 2017). Increase in Ab production and a decrease in Ab degrading enzymes possibly leads to Ab aggregation. These leads to NFTs formation and neurodegeneration. APP accumulation causes Ab deposition, leading to cognitive impairment (Selkoe and Hardy, 2016). Therefore, reducing Ab deposition is one of the ways to treat AD.

Anti-Apoptosis Effect
Apoptosis is an active regulation process of cell death, and inducing apoptosis is an important part of Ab-induced cell toxicity. Three major apoptotic pathways include mitochondrial pathway, endoplasmic reticulum pathway, and death receptors pathway. Mitochondrial pathway occurs mainly through reversing the mitochondrial membrane and the expression of cytochrome c (CytC). Endoplasmic reticulum pathway is mainly caused by Ca 2 + imbalance, which disrupts normal endoplasmic reticulum activities, causing an overload response in the endoplasmic reticulum, triggering the caspase receptor pathway cascade by activating caspase-3 and caspase-9 . Generally, apoptosis occurs mainly through the cytochrome c/caspase-9 pathway and the caspase-8 pathway. When the cell receives signals to induce apoptosis, the expression of Bax in the outer membrane increases, accelerating CytC activity, leading to caspase-3 and caspase-9 activation (Nguyen et al., 2013). Apoptosis is a key link in Ab-induced cytotoxicity, thus anti-apoptosis is recognized as an important way to treat AD. FIGURE 2 | Schematic diagram of autophagy, neuroinflammation, oxidative stress, mitochondrial dysfunction and apoptotic in AD. Autophagy is positive in alleviating AD through promoting Ab degradation, but hyperactive autophagy is harmful to neuron survival (A). The depositions of Ab activates the astrocytes and microglia which would secrete oxidative species, such as nitric oxide, and pro-inflammatory cytokines (B). Cytokines on the cell surface and activate pro-apoptotic signaling cascades. Mitochondrial dysfunction cause mitochondria to produce elevated levels of reactive oxygen and nitrogen species (ROS and RNS). Enhancement of ROS and RNS aggravates mitochondrial dysfunction (C, D), finally causing release of the pro-apoptotic signaling protein, CytC. CytC contributes to formation of the apoptosome (D). These factors all cause death of neuronal populations and lead to neurodegenerative disease.

Induce or Attenuate Autophagy Effect
Autophagy is a self-degradative process and a pervasive lysosomal degradation pathway to eliminate damaged organelles and proteins common in neurons. The process of autophagy can lead to recycling of cell material and homeostasis preservation (Rami, 2009;Hensley and Harris-White, 2015). The pathways involved in the regulation of autophagy are very complex, including phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, AMP-activated protein kinase (AMPK) pathway, renin-angiotensyns-tem (RAS)/cyclic adenosine monophosphate (cAMP)/proteinkinase A (PKA) pathway, p53 pathway, Class I PI3K/PKB pathway, and PI3K III pathway. These pathways are associated with most neurodegenerative diseases including AD. Recent studies suggest that autophagy plays an important role in Ab clearance. Ab-containing autophagosomes bind to lysosomes and causes Ab to degrade during autophagy (Xue et al., 2014). Not only is the APP protein processing related to autophagy, but the clearance of Ab deposition and maintenance of neuron function is too closely related to autophagy (Pickford et al., 2008).
Overloaded Ab leads to the activation of astrocytes and microglia and produces these factors. Neural inflammation in AD involves several important signaling pathways such as Toll-like receptor4 (TLR4) pathway and nuclear factor kappa B (NF-kB) pathway. TLR4-mediated signaling pathway comprises of two pathways: MyD88-dependent pathway and TRIF-dependent pathway. Currently, it is believed that proinflammatory cytokines activate microglial cells through TLR4 receptor. NF-kB is a common pathway for multiple signaling pathways that lead to inflammation and also a critical transcription factor involved in AD inflammatory processes (Granic et al., 2009). These suggest that inhibition of neuroinflammation and the NF-kB pathways is an effective way to treat AD.

Reduce Oxidative Stress
Oxidative stress is another important factor in the AD pathogenesis. TCM containing antioxidants reduces the risk of AD by inhibiting oxidative stress (Min and Min, 2014;Fan et al., 2017). Oxidative stress leads to excess reactive oxygen species (ROS) generation and DNA oxidation, and inhibits antioxidant substances, such as super oxide dismutase (SOD), glutathione peroxidase (GSH-Px). Enhancing ROS and nitrogen species (RNS) aggravates mitochondrial dysfunction and has a detrimental effect on the cellular DNA, proteins, and lipids.
Deposited Ab causes oxidative stress, subsequently increasing ROS levels (Miranda et al., 2000;Butterfield et al., 2006). Consequently, the high level of ROS and RNS lead to release of pro-apoptotic signaling protein, CytC. CytC accelerates the formation of apoptosome, causing neurodegenerative disease (Bhat et al., 2015).

Reduce Mitochondrial Dysfunction
Mitochondrial dysfunction is another important factor in AD pathogenesis. Extracellular deposits of Ab can access inside mitochondria and disrupt the normal state of mitochondria, leading to imbalanced mitochondrial membrane potential. The aggregation of Ab in extracellular are associated with mitochondrial dysfunction and neuronal structural damage. Mitochondrial damage leads to the loss of adenosine triphosphate (ATP) and ROS increase, leading to the cell apoptosis (Reddy and Beal, 2008;Moreira et al., 2010;Onyango et al., 2016).

Ginseng Protein
Ginseng (Panax ginseng C.A. Meyer), which belongs to the Araliaceae family. In China, ginseng has a long history of use to prolong life and soothe the puzzle. It exhibits strong therapeutic effects on cognitive impairments and neurodegeneration (Huang et al., 2019a). Ginsenosides are considered the main bioactive constituent of ginseng, and some studies have reported their neuroprotective effect . Recent research indicates that ginseng protein (GP) has a very significant neuroprotective effect in the treatment of AD. It inhibits Ab1-42 and tau pathology, increases the mRNA and protein expression of PI3K, p-Akt/Akt, and Bcl-2 (B-cell lymphoma 2)/Bax (Bcl-2 associated X) in the hippocampus. GP improves the memory capacity and cognitive function by activating PI3K/Akt signaling pathway (Li et al., 2016a).
The Total Flavonoid Extract from Dracoephalum moldavica L.
Dracoephalum moldavica L., a member of Lamiaceae family, possesses important medicinal value on refreshing body and mind as well as relieving sore throat and cough. In addition, D. moldavica has strong clinical effects on asthma, cardiovascular, and cerebral ischemia (Martínez-Vázquez et al., 2012). The flavonoids in D. moldavica have been a hotspot due to their extensive biological applications. The total flavonoid extract from D. moldavica (TFDM) mainly include apigenin, luteolin, acacetin, gardenin B, serophulein, salvigenin, isorhamnetin, tilianin, agastachoside, and kaempferol. These extracts are flavone, flavonol, and glycosides. The linked sugars are glucose, xylose, and their derivatives. TFDM are extracted from the aerial part of D. moldavica . A recent research revealed that TFDM treatment improved the memory capacity and inhibited neurodegeneration. TFDM decreased insoluble Ab levels by reducing Ab deposition and enhanced the antioxidant defense capacity. TFDM inhibited Ab production pathway, which is related to the down-regulation of b-secretase and b-C-terminal fragments in the brain of APP/PS1 mice. TFDM treatment activated the nuclear translocation of phosphoextracellular signal-regulated kinase 1/2 (ERK1/2) that led to elevated brain-derived neurotrophic factor (BDNF) levels through enhanced cAMP response element-binding protein (CREB) activation. TFDM can protect injured cells, and is associated with reducing APP and Ab 1-42 levels, hence exerts beneficial effects .

Safflower Yellow
SY is the main active chalcone glycoside compound extracted from Carthamus tinctorius L. (safflower), and belongs to Compositae or Asteraceae family. It is widely used in TCM for management of dysmenorrhea, amenorrhea, and joint pain. Besides, safflower seeds have been reported to attenuate memory impairment (Kim et al., 2019). SY improved cognitive functions and ameliorated the memory loss of APP/PS1 mice. SY decreased the level of Ab and overactivation of astrocytes in AD rats. Meanwhile, SY increased SOD and GSH-Px levels, and decreased malondialdehyde (MDA) and acetylcholinesterase (AChE) expression in brain tissues of AD mouse model. Moreover, SY was able to inhibit cyclin-dependent kinase 5 (CDK-5) and glycogen synthase kinase-3 (GSK-3) signaling pathways, which are upregulated in AD mouse model (Ma et al., 2015).

Emodin
Emodin is the main anthraquinone compound from Rheum officinale Baill. (Polygonaceae family) is extensively used in TCM and is the monarch drug in some TCM prescriptions with brain protection properties, such as Tiao-wei-cheng-qi Decoction, Da-cheng-qi Decoction (Gong et al., 2011). Emodin suppresses Ab deposition and tau phosphorylation. Furthermore, emodin downregulates the activity of b-site APPcleaving enzyme 1 (BACE1) and increases protein phosphatase 2A levels (Zeng et al., 2019).

Onjisaponin B
Onjisaponin B is the main active saponin constituent from Radix Polygalae. Radix Polygalae (the root of Polygala tenuifolia Willd.) belongs to Polygalaceae family and is a typical herbal medicine and has been extensively used for the treatment of dementia. Radix Polygalae plays an important role in most nootropics prescriptions (Zhang et al., 2008;Wang et al., 2015a;Wang et al., 2015b). Onjisaponin B reduces Ab production without directly inhibiting of BACE1 and g-secretase activities, promoting APP degradation (Li et al., 2016b) (Table 1).

Curcumin
Curcumin is an active polyphenol extraction isolated from Curcuma longa L. It is a member of ginger family and is important TCM with a variety of pharmacological activities, such as anti-inflammatory, anti-cancer, and dementia prevention. Several studies have shown that C. longa is a potential neuroprotective drug (Witkin and Li, 2013). Curcumin significantly decreased Ab-induced cytotoxicity by inhibiting mitochondria-mediated apoptosis via regulation of Bcl-2 family. Curcumin inhibited Ab-induced DNA damage by reducing of ROS generation through p38 MAPK and AKT pathways. Curcumin treatment also protected rat PC12 cells from Ab 25-35 -induced reduction in cell viability, the level of lactate dehydrogenase (LDH) and MDA. This process was associated with high expression of N-methyl-D-aspartate receptor (NMDAR) and NMDAR subunit 2A (NR2A) (Fan et al., 2017). Furthermore, curcumin was found to protect neuronal cell effectively and attenuate apoptosis by regulating intracellular Ca 2+ release, ROS, and mitochondrial membrane potential depolarization level in SH-SY5Y cells (Uğuz et al., 2016).

Triptolide
Triptolide is the main natural diterpene extracted from Tripterygium wilfordii Hook F. belonging to Celastraceae family, has been used in TCM for centuries. Recently, several reviews are published on T. wilfordii that exhibits therapeutic efficacies in the treatment of neurodegenerative diseases (Schwartz and Deczkowska, 2016). Triptolide remarkably inhibited the neuronal cells apoptosis and increased intracellular Ca 2+ concentration induced by Ab and Ab 25-35 . Triptolide effectively ameliorates Ab-induced cell injury by suppressing Ab levels and chemokine receptor 2 (CXCR2) activity (Gu et al., 2004;Wang et al., 2015a).

Crocin
Crocin is a bioactive carotenoid extracted from Crocus sativus L. (Iridaceae family) and is an important TCM known for its medicinal properties in neuropsychiatric disorders, such as depression, seizure, anxiety, and neurodegenerative disease. (Modabbernia and Akhondzadeh, 2013). Crocin can improve memory impairment and learning ability by reducing neuron apoptosis and Bax levels as well as increasing the expression of Bcl-2 in hippocampus and prefrontal cortical neurons (PFC) (Lin et al., 2019a). Ab administration in hippocampus significantly increases proteins and factors associated with autophagy and apoptosis, such as Beclin-1, LC3phosphatidylethanolamine conjugate (LC3-II)/cytosolic LC3 (LC3-I) ratio, Bax/Bcl-2 ratio, and cleaved caspase-3 (Asadi et al., 2015). Essentially, crocin alleviates malathion-induced neurological alterations and cognitive impairment by exerting its anti-apoptotic effects (Mohammadzadeh et al., 2019). These show that crocin has potential therapeutic effects on AD ( Table 2).

TCM FOR AD TREATMENT VIA AUTOPHAGY INDUCING OR ATTENUATION Berberine
Ber is an alkaloid extracted from Coptis chinensis Franch., a member of Ranunculaceae family extensively used in TCM. Coptis chinensis is a major ingredient of San-Huang-Xie-Xin-Tang, a traditional Chinese formula, used to manage cardiovascular and neurodegenerative diseases . Ber improves memory retention and spatial learning capacity by promoting Ab clearance. It exerts neuroprotective effect by facilitating autophagy through LC3-II, Beclin-1, hVps34, sequestosome 1 (p62), and Cathepsin-D activities as well as Bcl-2 brain levels reduction (Huang et al., 2017;Zhang et al., 2018).

Geniposide
Geniposide is an iridoid glycoside component of Gardenia jasminoides Ellis. and is an essential component of traditional phytomedicines . It belonging to Rubiaceae family, and is widely used in TCM. Geniposide exhibits significant therapeutic effect in the treatment of brain disorders and neurodegenerative disease (Zhao et al., 2016). Geniposide improved cognitive function by decreasing Ab 1-40 deposition in the brain tissue of AD mouse model by activating glucagon-like peptide-1 (GLP-1) receptors, which regulates mTOR. Thus, down-regulating mTOR signaling leading to enhanced cellular

b-Asarone
b-asarone is the major component of Acorus tatarinowii Schott (Wu and Fang, 2004). Acorus tatarinowii, belongs to Acoraceae family, is commonly used as TCM. It is known for a variety of pharmacological activities, specifically in treatment of neurodegenerative diseases . b-asarone increases cell viability by decreasing neuron specific enolase (NSE) levels and Beclin-1 in addition to Ab 1-42 -induced autophagy attenuation through Akt-mTOR signaling pathway (Xue et al., 2014).

Dendrobium nobile Lindl Alkaloids
Dendrobium nobile Lindl. has been used for medicinal purpose for centuries and is a member of Orchidaceae family. It has been widely used for kidney injury treatment. Alkaloids are considered as the main characteristic potent ingredients of D. nobile (Ng et al., 2012). Dendrobium nobile Lindl alkaloids (DNLA) is an active alkaloid from D. nobile Lindl. and mainly includes dendrobine, dendroxine, nobiline, dendrine, 6-hydroxydendroxine, N-methyl-dendrobine, and N-isopentenyldendrobine (Inubushi et al., 1964;Granelli et al., 1970). DNLA are able to increase autophagic flux, inhibit axonal degeneration by increasing Beclin-1 expression. DNLA increases autophagosome formation and autophagosome-lysosome fusion in hippocampus region .

Euxanthone
Euxanthone is a xanthone derivative extracted from Polygala caudata Rehder & E.H.Wilson mainly distributed in southwestern China that has been extensively used in TCM (Pan and Mao, 1984). uxanthone can attenuate memory impairment and learning dysfunction by reversing Ab 1-42induced neuronal apoptosis and autophagy. Euxanthone protected PC12 cells against Ab 1-42 -induced oxidative stress and apoptosis by inducing autophagy via LC3B-II enhancement and p62degradation (Yuan et al., 2018) (Table 3).

TCM FOR AD TREATMENT VIA ANTI-NEUROINFLAMMATION Gypenoside
Gypenoside is the major active saponin ingredient of Gynostemma pentaphyllum (Thunb.) Makino, a member of Cucurbitaceae family known for strengthening effect on the heart and brain (Lin et al., 1993). Recent researches have shown that Gypenoside has a potential in the treatment of neurodegenerative diseases. The deposition of Ab activated microglia and astrocyte, leading to the production of inflammatory factors, IL-1b, IL-6, and TNF-a which caused neuronal death (Kumar et al., 2018;Seo et al., 2018). Gypenoside attenuates Ab-induced inflammation by downregulating the release of proinflammatory factors such as iNOS, TNF-a, IL-1, and IL-6, as well as increasing anti-inflammatory factors release, such as IL-10. Gypenoside can increase the levels of arginase-1 (Arg-1) protein, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) secretions. The process is mediated by suppressing cell signaling protein 1 (SOCS1) (Cai et al., 2016).

Steroid-Enriched Fraction of Achyranthes bidentata Blume (ABS)
Achyranthes bidentata Blume (Amaranthaceae family) is commonly used in the treatment of dementia in TCM. The roots of A. bidentata are rich in pharmacological active ingredients (He et al., 2017). Recent reports have shown that ABS can attenuate cognitive dysfunction and neuroinflammation. ABS alone (50 mg/kg) reduced the levels of TNF-a in brain and decreased neuroinflammation by modulating ERK and NF-kB pathway Xu X. X. et al., 2017;Lin et al., 2019b).

Matrine
Matrine is the major bioactive alkaloid of the Sophora flavescens Ait. (Fabaceae family), a famous traditional Chinese herbal medicine used to treat dementia. Matrine can improve cognitive deficits and learning ability. Matrine attenuated Ab 42 -induced memory deficits, cytotoxicity, and the formation of senile plaques in AD transgenic mice. This was through reducing Ab deposition and proinflammatory cytokines via glycation end products (RAGE) signaling pathway (Cui et al., 2017).

Scutellarein
Scutellarein is a natural ingredient extracted from Scutellaria baicalensis Georgi., and belongs to Lamiaceae family. It has been traditionally used to treat various diseases, including dementia. Recent reports revealed that flavonoids from S. baicalensis, such as baicalin, baicalein, and scutellarin, exert neuroprotective effects . Scutellarein, a hydrolysate of scutellarin, can also decrease hippocampal Ab and MDA content while increasing superoxide dismutase (SOD) and acetylcholine (Ach) expression. Moreover, it has a protective effect on Ab-exposed apoptosis, counteracts the Ab-induced Bcl-2 expression decrease and inhibits the expression of Bax and cleaved caspase3. In PC12 cells, scutellarein attenuated Ab-induced cell death, cognitive impairment, hippocampal alterations, hippocampal neuroinflammation, and NF-kB activation. In summary, scutellarein inhibited Ab−induced PC12 cell apoptosis. This demonstrated that scutellarein has potential therapeutic application in AD (Huang et al., 2019b).

Oridonin
Oridonin (Ori) is the main active diterpenoid of Isodon rubescens (Hemsl.) H. Hara (syn. Rabdosia rubescens Hara) of Lamiaceae family and has been used as Chinese herbal medicine due to its biological activities (Zhang et al., 2004). Ori has been shown to attenuate memory impairment and has anti-inflammatory effects. Ori exerts anti-inflammatory effects by inhibiting the activation of glial, decreasing the release of inflammatory cytokines IL-1b, IL-6, and TNF-a. This process is potentially associated with the NF-kB pathway inhibition (Wang et al., 2014).

Diammonium Glycyrrhizinate
Diammonium glycyrrhizinate (DG) is the most important active ingredient of Glycyrrhiza uralensis Fisch. ex DC. of the Fabaceae family. It has been widely used in TCM to treat variety of diseases. Recent pharmacological reports revealed that G. uralensis exerts neuroprotective effect in AD (Ahn et al., 2006). DG attenuated Ab 1-42 -induced memory impairment and activation of microglia and inflammation in AD mice model by inhibiting the activation of MAPK and NF-kB signaling pathways (Zhao et al., 2013) (Table 4).

TCM FOR AD TREATMENT VIA REDUCING OXIDATIVE STRESS Schisanhenol
Schisanhenol is a lignan compound from Schisandra sphenanthera Rehder & E. H. Wilson of Schisandraceae family. It has been used extensively in TCM to treat age-related diseases (Hung et al., 2007). Schisanhenol can remove oxygen radicals and inhibit lipid peroxidation and apoptotic cell death induced by oxidative stress. In addition, schisanhenol can improve learning and memory as well as attenuate oxidative damage by reducing the activity of AChE via sirtuin 1 (SIRT1)-coactivator 1-a (PGC-1a)-Tau signaling pathway (Yu and Liu, 2008;Han et al., 2019).  Zhao et al., 2013 Amentoflavone (AF) AF is the major active flavonoid found in Selaginella tamariscina (P. Beauv.) Spring. This plant belongs to Schisandraceae family which has been found exert pleiotropic bioactivities. Recent pharmacological reports provide evidence that S. tamariscina could be an effective neuroprotective agent (Shin et al., 2006). It was found that AF decreased Ab-induced learning and memory deficits and prevented neuronal cell apoptosis, oxidative stress in the hippocampus of rat model. AF increased Nrf2 expression and promoted AMPK signaling. The neuroprotective effect of AF against Ab 1-42 -induced neurotoxicity is mediated by Nrf2 antioxidant pathways and AMPK signaling (Chen et al., 2018a).

Oxymatrine
Oxymatrine (OMT) is a bioactive quinolizidine alkaloid isolated from Sophora flavescens Aiton and Sophora alopecuroides L. (Qian et al., 2018). A study found that OMT significantly increased cell viability and the cognitive ability of rats. Moreover, treatment with OMT increased the ratio of Bcl-2/Bax and decreased the expression of caspase-3. The protective effect of OMT against Ab 1-42 -induced neuronal toxicity was linked to the inhibition of MAPK and NF-kB signal pathways .

Shikonin
Shikonin is an active naphthoquinone ingredient found in Lithospermum erythrorhizon Siebold & Zucc., one of the most important Chinese herbal medicine belonging to the Boraginaceae family. This compound has long been used to treat allergic diseases. Recent reports have provided evidence that roots of L. erythrorhizon contain compounds with antioxidant activities (Papageorgiou et al., 2008;Yoshida et al., 2014). Shikonin markedly increased cell viability by upregulating the activity of SOD catalase and GSH-Px. It also decreased levels of MDA and ROS, and stabilized the mitochondrial membrane potential in Ab 1-42 -treated PC12 cells. The neuroprotective effect of shikonin against Ab-induced cell damage was due to inhibition of cleaved caspase-3 activity and reduction in ratio of Bcl-2/Bax all of which prevent antioxidants and apoptosis (Tong et al., 2018).

Linalool (LI)
LI is the main volatile monoterpene compound found in several aromatic plants, such as Lavandula angustifolia Mill., Rosmarinus officinalis L. and Coriandrum sativum L. (Kuroda et al., 2005;Batista et al., 2010;Gastón et al., 2016). In a previous study, LI significantly improved the cognitive performance and alleviated Ab 1-40 -induced cell injury by increasing the levels of oxidative stress indicators such as SOD, GPX, and AChE. LI decreased the activity of cleaved caspase-3 and caspase-9 and increased the expression level of Nrf2 and heme oxygenase-1 (HO-1). Thus, LI confers neuroprotection by preventing apoptosis, oxidative stress, and activation of Nrf2/HO-1 signaling pathway (Xu P. et al., 2017).

Schisandrin C
Schisandrin C (SCH-C) is the main antioxidative lignan extracted from Schisandra chinensis (Trucz.) Baill. It attenuated impaired cognitive and learning ability by decreasing the activity of total cholinesterase (ChEtotal), significantly increasing the activities of SOD and GSH-Px glutathione. Thus, neuroprotective effect of SCH-C against Ab 1-42 -induced cell injury is mediated by inhibition of ChEtotal and upregulation of the level of SOD and GSH-Px glutathione (Mao et al., 2015).

Acteoside
Acteoside, a phenylethanoid glycoside, is isolated from Cistanche deserticoLa Y. C. Ma. that belongs to Drobanchaceae family. It has been used to treat age-related disorders and improve kidney function (Jiang and Tu, 2009). Acteoside improved the cognitive function following treatment with D-galactose (D-gal) and AlCl 3 by increasing the number of neurons and decreasing the level of nitric oxide (NO), nitric oxide synthase (NOS) and caspase-3 protein expression in hippocampal tissues. The mechanisms associated include suppression of oxidative stress and hence neuronal apoptosis (Peng et al., 2015).

Vanillic Acid
Vanillic acid (VA) is a natural benzoic acid derivative obtained from Angelica sinensis (Oliv.) Diels. which belongs to Apiaceae family. It has been used in TCM as a flavoring agent and to treat various diseases. Recent studies have provided evidence that Danggui Buxue Tang (derived from A. sinensis (Oliv.) Diels) has the potential to treat AD (Gong et al., 2019). VA significantly improved memory function by decreasing AChE, corticosterone, TNF-a, and inhibiting oxidative stress (Singh et al., 2015).

Protosappanin A
Protosappanin A (PTA) is the major biphenyl compound extracted from Caesalpinia sappan L. (Lignum Sappan), a member of Fabaceae family. This plant has traditionally been used to treat various diseases. Numerous lines of evidence also show that compounds found in Biancaea sappan (L.) Tod. (syn. Caesalpinia sappan L.) have antioxidant activities (Sasaki et al., 2007). Activation of microglia increases the level of ROS and NO, leading to neuronal and cell injury. PTA exerted immunosuppressive effects and anti-oxidative activities against lipopolysaccharide (LPS)-induced injury on BV-2 microglia by inhibiting the activation of microglia and suppressing ROS and NO levels. Moreover, PTA modulated the CD14/TLR4-dependent IkB-kinase (IKK)/nuclear factor kB (IkB)/NF-kB inflammation signaling pathway which decreased the expression of NADPH oxidase and iNOS (Zeng et al., 2012).

Salidroside
Salidroside is the main tyrosol-glucoside compound extracted from Rhodiola rosea L. that belongs to Crassulaceae family.

TCM IMPROVES AD BY CORRECTING MITOCHONDRIAL DYSFUNCTION Icariin
Icariin is the principal flavonoid in Epimedium brevicornu Maxim. This plant is a member of the Berberidaceae family commonly used to formulate Chinese herbal drugs for various diseases. Accumulating evidence demonstrates that E. brevicornu confer beneficial effects on the nervous systems (Ma et al., 2011). Icariin administration effectively decreased Ab deposition in mitochondria and reversed the decline in levels of pyruvate dehydrogenase component a (PDHE1a) and cytochrome c oxidase IV (COX IV) in 3×Tg-AD mice. In summary, Icariin improves cognitive functions and neuronal cell activity, enhancing electron transport chain, N-acetylaspartate level, and brain ATP metabolism (Lustbader et al., 2004;Reddy and Beal, 2008;Chen et al., 2016).

Salvianolic Acid B
Salvianolic acid B (SalB) is the main active polyphenol found in Salvia miltiorrhiza Bge. a member of Lamiaceae family. Epidemiological evidence demonstrates that the roots of S. miltiorrhiza contain pharmacologically active ingredients with curative potential for various diseases, including AD . It was previously found that SalB alleviated Abinduced increase in glutathione (GSH) activity, lipid oxidation, axonal mitochondrial fragmentation, stabilized mitochondrial membrane potential, improved ATP production, and activity of CytC oxidase, all of which prevented cytotoxicity. Administration of SalB restores the synaptic density of Abtreated neurons .

Ligustilide
Ligustilide (LIG) is the main bioactive lipophilic component of Radix angelicae sinensis, Angelica sinensis (Oliv.) Diels. LIG reduces Ab expression and that of dynamin-related protein 1 (Drp1) and increases levels of mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and Optic atrophy 1(Opa1) in APP/PS1 transgenic mice. LIG exerts anti-oxidant effects by decreasing MDA and ROS levels while increasing the level of Mn-SOD. It also improves memory deficits and mitochondrial function in APP/PS1 mice by reducing Ab levels, enhancing mitochondrial motility, and restoring synaptic structure .

Tetrahydroxy Stilbene Glycoside
Tetrahydroxy stilbene glycoside (TSG) is one of the active polyhydroxystibene component isolated from Reynoutria multiflora (Thunb.) Moldenke (syn. Polygonum multiflorum), a member of the Polygonaceae family. It has been used to treat liver and kidney injury and as an antiaging agent for centuries. Recent reports show that TSG improves cognitive deficits in AD . It also alleviates cell oxidative stress injury by attenuating LDH release, ROS production, and MDA leakage. TSG canceled Ab-induced loss of MMP, alleviated the release of CytC from mitochondria to cytosol. It also increases the activity of caspase-3 and Bax expression, whereas it decreases Bcl-2 expression. TSG prevents neuronal cell injury by stabilizing mitochondrial function via Nrf2-HO-1 pathway (Jiao et al., 2017).

Hopeahainol A
Hopeahainol A (Hop A) is a potential AChE inhibitor and antioxidative polyphenol isolated from Hopea hainanensis Merrill & Chun. A previous study revealed that Hop A not only suppressed Ab levels, but also inhibited the interaction between Ab1-42 and Ab-bound alcohol dehydrogenase (ABAD), which partially improved mitochondrial function and oxidative damage. These results reveal that Hop A balances synaptic function and improves memory deficits in APP/PS1 mice. (Zhu et al., 2013) ( Table 6).

CONCLUSIONS
AD is a progressive neurodegenerative disease characterized by progressive loss of memory and cognitive function. Several studies have investigated the pathogenesis of AD in order to develop strategies to treat AD. So far, it has been reported that b-Amyloid, apoptosis, autophagy, neuroinflammation, oxidative stress, and mitochondrial dysfunction participate in the pathogenesis of AD. The current drugs used to control symptoms of AD are often accompanied by side effects and are not sufficiently effective. This is because the of pathogenesis is complicated and is not fully understood. Recent research has provided evidence that natural active ingredients in TCM drugs have multi-target therapeutic effects. Thus, important active monomers and bioactive compounds extracted from TCM herbs have the potential to be new drugs for treating AD. We show that a variety of bioactive components from TCM such as Polygala tenuifolia, Tripterygium wilfordii, Andrographis paniculata, Gynostemma pentaphyllum, Schisandra sphenanthera, and Reynoutria multiflora can improve AD. The monomers and extracts of TCM mentioned in this paper regulate AD by decreasing b-Amyloid production, autophagy, apoptosis, neuroinflammation, oxidative stress as well as mitochondrial dysfunction ( Figure 3).
In this study, we found that compounds extracted from Lamiaceae family are potential treatments for AD. For example, Dracoephalum moldavica L., suppresses AD progression by reducing Ab production, whereas Scutellaria baicalensis Georgi. and Isodon rubescens (Hemsl.) H.Hara improve AD by preventing neuroinflammation. Lavandula angustifolia Mill. and Rosmarinus officinalis L. confer therapeutic benefits on AD by reducing oxidative stress whereas Salvia miltiorrhiza Bge. suppresses the progression of AD by resolving mitochondrial dysfunction. This may be associated with this plant contains aromatic oils and other active ingredients. In addition, extracts from Fabaceae family and Polygonaceae family have beneficial effects on AD. It should be noted that TCM exhibit multi-target, multi-pathway, and multi-system characteristics, and their monomers have same mechanism of action but different structures. Among TCM compounds, flavonoids, alkaloids, and polyphenols have the most significant effects on AD. Further studies are advocated to explore further mechanisms of these drugs on AD.

AUTHOR CONTRIBUTIONS
S-YC and YG prepared the draft manuscript. J-YS and DY searched the database and extracted literature. L-HF summarized all the tables. LX, PW, and X-LM revised the manuscript. All authors read and approved the manuscript.