Arch Pharm Res Vol 33, No 10, 1589-1609, 2010 DOI 10.

1007/s12272-010-1010-y

REVIEW

Potential Therapeutic Agents against Alzheimer's Disease from Natural Sources

So-Young Park
Department of Nanobiomedical Science, College of Advanced Science, Dankook University, Cheonan 330-714, Korea
(Received August 8, 2010/Revised August 17, 2010/Accepted August 18, 2010)

The average human life span in developed countries has increased to more than 80 years following rapid breakthrough and developments in modern medicine and science, resulting in prolonged life expectancy and increase in the population counts of the geriatric age group. This translates into a dramatic increase in disease burden of elderly patients suffering from senile disorders including neurodegenerative diseases, particularly Alzheimers disease (AD). AD is characterized by the death of nerve cells in the cerebral cortex and is the most common subtype of dementia that affected 25 million people worldwide in 2000 and is expected to increase to 114 million by 2050. Despite the exponential growth in the number of AD patients, only acetylcholinesterase (AChE) inhibitors are being currently used to treat AD. It is well known that AChE inhibitors can alleviate the symptoms of AD but not halt the disease progression. Consequently, therapeutic agents against AD acting at various pathologic levels are needed. In the recent decade, natural products with anti-AD properties have attracted much attention. But very few natural products have been investigated in a scientifically justifiable method for these biological activities. Following a detailed research process, it is certain that natural products have a strong potential to develop biologically active compounds with new chemical structures. Many studies have been carried out to identify the naturally occurring anti-AD agents. This review article describes the molecular targets aiming at developing the anti-AD agents including the inhibition of AChE, inhibition of A production by enhancing secretase (non-amyloidogenic pathway) or inhibiting - and -secretases (amyloidogenic pathway), alleviating A-induced neurotoxicity or reducing A-induced neuroinflammation. In addition, this paper summarizes the potential of some of the natural products that might inhibit specific molecular targets and slow the progression of this disease. Key words: Alzheimers disease, Therapeutics, Natural products, Beta-amyloid (A)

INTRODUCTION
In the early 1900s, average human life span was a meager 40 years. However, the advent of modern technology and path-breaking developments in medicine and science has lead to drastic improvements in quality of life especially in the developed countries and the life expectancy has now extended to about 80 years by the year 2000. In a recent International Conference Tomorrows People: The Challenges of Technologies for Life Extension and Enhancement
Correspondence to: So-Young Park, Department of Nanobiomedical Science, College of Advanced Science, Dankook University, Chungnam 330-714, Korea Tel: 82-41-550-3691, Fax: 82-41-550-3409 E-mail: soypark23@dankook.ac.kr

held in 2006, England, one of the speakers, Dr. Grey at Cambridge University reported that the average life span will reach 120 years old within 60 years, suggesting a dramatic increase in the quantum of elderly population in the future. In other words, increased life expectancy is related directly to the increased number of elderly people and proportionately raising the occurrence of senile disorders including neurodegenerative diseases. Neurodegenerative diseases are a group of disease conditions that result from chronic breakdown and progressive functional or structural loss of the neurons, particularly of the central nervous system (CNS). The accumulation of aggregated proteins in neurons has been implicated in these types of diseases and progression is caused by neurodegeneration. Alzheimers

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disease (AD) is one of the most well-known diseases that follow this process. AD was first reported by a German physician, Alois Alzheimer in 1907, and is the most common subtype of dementia and a neurodegenerative disease characterized by the death of nerve cells in the cerebral cortex. The disease affects 25 million people worldwide in 2000 and it is expected to increase to 114 million by 2050 (Wimo et al., 2003). AD affects one in three individual over the age of 85 years (Hebert et al., 2003). AD in the early stages presents with a decline in cognitive function, particularly short term memory. As the disease progresses, patients complain of problems in reading, speaking and logical thinking, and long-term memory is also impaired. In the later stages of the disease, language deficits, depression, aggression, agitation and psychosis are commonly observed in AD patients. As the disease progresses further, patients eventually depends for total care from caregivers.

ALZHEIMERS DISEASE (AD)

AD has two characteristic pathologic hallmarks, senile plaques (SPs) and neurofibrillary tangles (NFTs). SPs are an extracellular accumulation of beta-amyloid (A) surrounded by dystrophic neurites and microglia. A originates from the proteolysis of the amyloid precursor protein (APP) through sequential cleavage by beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1, -secretase) and -secretase (Selko, 1997). The excessive production of A or decreased A clearance leads to the accumulation and aggregation of A, which is toxic to cells (Selkoe, 2001; Tanzi and Bertram, 2005). High amounts of this toxic A is believed to be a major cause of AD pathology (amyloid hypothesis) (Kawahara and Kuroda, 2000). Genetic mutations at the cleavage sites in APP was the etiology behind the familial Alzheimers disease found in a Swedish family. This family showed early disease progression to as early as 30 years. The cause of AD in this Swedish family is implicated for the increased production of A and the aggregation of A to oligomers. Soluble, monomeric A self-aggregates into multiple forms including oligomers (2 to 6 peptides), fibrils and -pleated sheets (insoluble fibers). Among them, oligomers of A are the most neurotoxic (Walsh and Selkoe, 2007). The fact that the severity of cognitive impairment correlates well with the levels of A oligomers, while the total A burden in AD patients does not, support the importance of A oligomers in the AD pathology (Lue et al., 1999). Aggregated A oligomers stimulate an array of biological signaling pathways by direct or indirect interactions with neuronal membranes and cause

oxidative stress and inflammatory responses, which leads to an impairment of the neuronal synapses and dendrites (Heneka and O'Banion, 2007; Roberson and Mucke, 2006). The accumulation of A eventually causes the pathological characteristics of AD, including neuronal loss and disintegration of the neural circuits. On the other hand, the presence of neurofibrillar tangles (NFTs) is another pathological hallmark of AD. NFTs are the intraneuronal accumulation of paired helical filaments (PHFs) with hyperphosphorylated tau being the major protein subunits of PHFs (Kosik et al., 1986; Wood et al., 1986; Kondo et al., 1988). Normally, the tau protein is abundant in neurons of the CNS. The tau protein promotes the assembly of tubulin to microtubules, and stabilizes microtubules and vesicle transport. However, hyperphosphorylation of tau makes it insoluble, and drastically decreases the affinity in microtubules. Therefore, instead of promoting microtubule assembly, it aggregates itself to PHFs (Iqbal et al., 2009). In contrast to A, there is no genetic mutation of tau in AD, but the degree of cognitive decline in AD patients correlates significantly with the levels of phosphorylated tau and total tau in the cerebrospinal fluid (Wallin et al., 2006). In addition, experimental evidence indicates that A also acts by inducing an increased phosphorylation of tau at the disease-relevant sites (Busciglio et al., 1995; Greenberg and Kosik, 1995; Takashima et al., 1998; Zheng et al., 2002), and can cause tau aggregation into PHF-like filaments (Rank et al., 2002). A-Induced neurodegeneration in cultured neurons or A-induced cognitive deterioration in mice mandates phosphorylation of the tau protein (Rapoport et al., 2002; Roberson et al., 2007). The hyperphosphorylated tau-induced neurotoxicity occurs downstream of A and tau phosphorylation is considered as the limiting factor in Ainduced cell death (Leschik et al., 2007). This suggests that tau phosphorylation plays a key role in the disease progression of AD induced by A.

THERAPEUTIC AGENTS AVAILABLE FOR AD

The agents used in pharmacotherapy of AD are the acetylcholinesterase (AChE) inhibitors, which were the first approved medication for the treatment of AD. Postmortem studies of the brains in AD patients revealed lower levels of the neurotransmitter, acetylcholine (ACh) and the enzyme choline acetyl transferase (ChAT). A shortage of ACh in the brain shows a strong correlation with the deteriorated cognitive function in AD patients (Francis et al., 1999). To increase the

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Table I. AChE inhibitors approved by US FDA for the treatment of AD General name Tacrine Donepezil Rivastigmine Galantamine Brand name Cognex Aricept Exelon Razadyne Side effects Primarily hepatotoxicity. In addition, nausea, indigestion, vomiting, diarrhea, abdominal pain, skin rash Headache, generalized pain, fatigue, dizziness, nausea, vomiting, diarrhea, anorexia, weight loss, muscle cramping, insomnia Weight loss, anorexia, dizziness Nausea, vomiting, diarrhea, anorexia, weight loss, vascular disease (heart attack, stroke)

neurotransmitter ACh in the synapses, synthetic compounds that inhibit AChE, an enzyme responsible for the breakdown of ACh in the nerve terminals, was introduced in clinics (Table I). Tacrine was the first U.S. Food and Drug Administration (FDA)-approved AChE inhibitor for the treatment of cognitive loss in AD patients since 1993. Since then, several other AChE inhibitors have been approved by the US FDA including donepezil in 1996, rivastigmine in 2000, and galantamine in 2001 (van Marum, 2008). AChE inhibitors can help alleviate the cognitive symptoms of AD patients, but they do not halt or delay the disease progression. In addition, they are accompanied with unwanted side effects such as nausea, diarrhea and hepatotoxicity, and have a limited utility in AD patients due to their poor oral bioavailability (Lleo et al., 2006). In addition, cholinergic and nicotinic agonists have been proposed to increase ACh release in nerve terminals but these are not as effective as AChE inhibitors as far as therapeutic effectiveness is concerned. More recently glutamate-mediated neurotoxicity was proposed as a possible etiology and therapeutic target have been directed towards this pathway in the treatment of AD. Memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, has been approved for the treatment in AD from FDA in 2004 (Lipton, 2007). Memantine exerts its neuroprotective effect at least in part though the inhibition of excitotoxicity, which leads to neuronal injury or death though over-activation of the NMDA receptors by excessive exposure to neurotransmitter glutamate (Sonkusare et al., 2005). It was reported that memantine improved the language function and overall cognitive abilities significantly in moderate to severe AD patients (Ferris et al., 2009; Mecocci et al., 2009).

teomics and chemical genomics, which allowed the discovery of new molecular drug-targets. In addition, achievement of chemical diversity by combinatorial chemistry also leads to the discovery of a range of molecular targets to screen for potential therapeutic agents through high-throughput screens (Newman and Cragg, 2007). Despite the advances in extraction and isolation techniques practiced in natural product chemistry, there are few systemic approaches to be followed during the discovery of biologically active natural products. Furthermore, 63% of the low molecular drugs developed from 1981 to 2006 are natural products or natural product-derived compounds (Newman and Cragg, 2007). These reports suggest that natural products have strong potential to develop biological active compounds with anti-AD activity, but these natural products have attracted relatively little attention as a potentially valuable resource for drug discovery against AD. Only some natural sources such as Ginkgo biloba L. (Ginkgoaceae) and Huperzia serrata Trevis (Pteridophyta) have been studied extensively as natural therapeutic agents to treat AD patients. Therefore, it was envisioned that natural products may produce biologically active compounds against AD.

NATURAL PRODUCTS AS POTENTIAL THERAPEUTIC AGENTS TO TREAT AD

Recent advancement in pharmacology is based on the development of concepts such as genomics, pro-

Modulators of -, - and -secretases A is considered as a major cause of AD. A is a proteolytic product of APP by - and -secretases. APP is an evolutionary conserved type 1 transmembrane glycoprotein (Rosen et al., 1989). Although the precise function of APP is not known, it is believed that APP is involved in the development of CNS and stress or injury response (Panegyres, 2001). APP undergoes proteolytic processing through either non-amyloidogenic or amyloidogenic pathways (Nunan and Small, 2000). During the non-amyloidogenic pathway, APP is cleaved by membrane-bound enzyme -secretase within its A domain. This results in the release of extracellular secretion of soluble -secretase-cleaved sAPP fragments and the production of a short membrane bound COOH-terminal fragment, -CTF

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or C83, which precludes the formation of A (Esch et al., 1990) (Fig. 1). Subsequent cleavage of C83 by secretase induces the extracellular release of a 3-kDa peptide p3, whereas APP intracellular domain (AICD) is secreted into the cytoplasm (Cao and Sudhof, 2004). Therefore, any substances that can enhance the activity of -secretase can reduce the production of neurotoxic A and should be beneficial for the treatment of AD. In the amyloidogenic pathway, APP undergoes sequential proteolytic processing by - and -secretases. -Secretase (BACE1) cleaves APP at the N-terminal part of the A domain (Yan et al., 1999) (Fig. 1). This process releases extracellular sAPP fragments and retains the membrane bound -C-Terminal Fragment (-CTF) or C99 fragment. Subsequent cleavage of -

CTF (C99) by -secretase at the C-terminal part of the A domain releases APP in the intracellular domain (AICD) and secretes A to the extracellular spaces (Seubert et al., 1993). -Secretase is a membrane protein complex composed of presenilin (PS), nicastrin, Aph-1 and Pen-2. PS1 and PS2 are essential for secretase-induced proteolytic cleavage of APP, and mutations in PSs enhance the proteolytic processing of APP by -secretase thereby increasing the release of A in mice (Selkoe, 1998). Furthermore, families with mutations in PSs are associated with Familial Alzheimers Disease, which has an onset as early as their 30s (St George-Hyslop and Petit, 2005). Therefore, any agents that could modulate the - and secretases activities can suppress the cleavage of APP and subsequently the secretion of A would be desirable.

Fig. 1. Proteolytic processing of Amyloid Precursor Protein (APP) to beta-amyloid (A). The cleavage of APP by -secretase initiates the proteolytic process of APP in the center of the A domain and precludes the generation of A. This nonamyloidogenic process releases extracellular p3 proteins and the amyloid intracellular domain (AICD). Meanwhile, the cleavage of APP by -secretase leads to the release of extracellular secretion of soluble APP- (sAPP) and membrane-bound C99 fragment. The sequential cleavage of C99 fragment by -secretase generates AICD and A. The generated soluble and monomeric A undergoes self-aggregation and oligomers of A are the most toxic to neurons. Thus, the modulation of -, and -secretases activities, and A aggregation by any substances including natural products would be desirable for AD. For example, Ginkgo biloba extracts (EGb761) enhance the activity of -secretase (A: -secretase enhancer). Catechins in green tea and resveratrol derivatives inhibit the activity of -secretase (B: -secretase inhibitors), whereas DAPT and LY411375 inhibit that of -secretase (C: -secretase inhibitor). In addition, curcuminoids such as curcumin and demethoxycurcumin inhibit the aggregation of A into oligomers (D: A aggregation inhibitor).

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-Secretase enhancer Some natural products have been reported to enhance the non-amyloidogenic pathway. Garlic (Allium sativum L., Alliaceae) has been used for both culinary and medicinal purposes since ancient times. Garlic was reported to be beneficial to prevent heart disease including atherosclerosis, high cholesterol and high blood pressure and cancer. Garlic also reduces platelet aggregation, hyperlipidemia and blood sugar levels (Borek, 2006). In addition, Chauhan reported the beneficial effects of a garlic extract on AD (Chauhan, 2006). According to this report, garlic extracts, aged at room temperature for 20 months after extracting sliced fresh garlic with 20% aqueous ethanol, increased the -secretase-cleaved sAPP fragments by 58.9%. Aged garlic extracts also decreased the levels of soluble and fibrillar A and A-immunoreactive plaques by 2.3-3 and 1.67 fold, respectively, in an Alzheimers Swedish double mutant mouse model (Tg2576 mice). Among the major water-soluble and lipid-soluble constituents of the aged garlic extract, diallyl-disulfide (DADS, 1) and S-allyl-cysteine (SAC, 2) (Fig. 2) showed positive effects in reducing the levels of A production, but the degree of inhibition was slightly lower than aged garlic extracts, probably due to the synergistic effect of other multi-potent phytochemicals present in aged garlic extracts. In addition, aged garlic extracts ameliorated early cognitive impairment and prevented the aggravation of memory tasks in Tg2576 mice, which might be correlated with the Mild Cognitive Im-

Fig. 2. Structures of -secretase modulators

pairment (MCI) stage of AD (Chauhan and Sandoval, 2007). Epigallocatechin-3-gallate (EGCG, 3) (Fig. 2), the main phenolic constituent of green tea, reduces the cleavage of APP and the production of A in murine neuroblastoma cells (N2a) transfected with the human Swedish mutant APP. EGCG also inhibits the generation of A in primary neurons cultured from Tg2576 mice by promoting -secretase proteolytic process, thereby increasing the production of -secretasecleaved sAPP fragments (Rezai-Zadeh et al., 2005). Treatment of PS2 mutant AD mice with EGCG enhanced the activity of -secretase and reduced the activities of - and -secretases, subsequently decreasing the levels of A, which was accompanied by an improved memory function (Lee et al., 2009). These effects have been suggested to be mediated via the ERK and NF-B pathways in mice. The oral or intraperitoneal administration of EGCG to Tg2576 mice improved the working memory. The beneficial effect of EGCG in Tg2576 mice was accompanied by a significant decrease in the soluble and insoluble forms of the A and the A burden in the brain (Rezai-Zadeh et al., 2008). Long-term oral administration of A improved the spatial learning and memory and prevented the decrease in the proteins involved in the synaptic function and synaptic structure including brain-derived neurotrophic factor (BDNF) and post-synaptic density protein-95 (PSD95) (Li et al., 2009). Furthermore, EGCG and fish oil, which consists of omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), significantly enhance the activity of -secretase and the production of -secretasecleaved sAPP fragments in N2a cells. The co-administration of EGCG and fish oil has synergistic effects on the decrease in AD-like pathology in Tg2576 mice, suggesting the beneficial effects of EGCG and fish oil in the treatment of AD (Giunta et al., 2010). Omega-3 fatty acids, such as DHA (4) (Fig. 2) and EPA are also known to reduce the risk of AD in epidemiological studies (Kalmijn et al., 2004; Morris et al., 2003). In addition, DHA enhanced APP processing by increasing the -secretase activity to -secretasecleaved sAPP fragments and reduced A production. Hence, DHA reduces the overall plaque burden in Tg2576 mice (Lim et al., 2005). DHA is a polyunsaturated omega-3 fatty acid found in fish. The low levels of DHA in the blood have been linked to cognitive impairment, and changes in learning behavior in rats (Catalan et al., 2002; Ikemoto et al., 2001). A deficiency of DHA in plasma has been linked to cognitive decline in AD patients (Yurko-Mauro, 2010). In particular, a deficiency of DHA in the brain membranes of

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AD patients suggests the loss of protection from the free-radical mediated lipid peroxidation of the membranes (Montine et al., 2002). Cryptotanshinone (5) (Fig. 2) is a natural productderived -secretase enhancer, a diterpene isolated from the roots of Salvia miltiorrhiza Bunge (Laminaceae). S. miltiorrhiza has been used as traditional Chinese medicine to prevent cardiac diseases, arthritis and other inflammatory diseases (Gao et al., 1979). Recently, cryptotanshinone was reported to improve the learning and memory, and cognitive deficits in APP/PS1 mice (Kim et al., 2007), and the main molecular mechanisms responsible for the beneficial effects of cryptotanshinone on the AD-like pathology was the reduced production of A and increased secretase-cleaved sAPP fragments through the enhanced -secretase activity (Mei et al., 2009), suggesting that cryptotanshinone has good therapeutic potential for AD. Ginkgo biloba extracts (EGb761) (Ginkgoaceae) are another class of well-known natural product in clinical studies for AD. EGb761 was reported to enhance the cognitive function in AD, but the precise mechanism of its pharmacological effects is unclear. However, it was reported that EGb761 increased the release of secretase-cleaved sAPP fragments, but the expression of -secretase was unaffected by EGb761, suggesting that EGb761 increases the APP metabolism to produce sAPP fragments by activating the nonamyloidogenic pathway (Colciaghi et al., 2004). L-3-n-Butylphthalide isolated from Apium graveolens L. (Apiaceae) was reported to be neuroprotective in cultured neuronal cells, in ischemic and A-infused animal models (Peng et al., 2008; Peng et al., 2009). Recently, L-3-n-butylphthalide was reported to display beneficial effects on learning and memory in tripletransgenic AD mice. L-3-n-Butylphthalide significantly improved the cognitive deficits, which was accompanied by a reduced A burden (Peng et al., 2009) in the brain. The decrease in the A burden might be related to the enhancement of -secretase-cleaved-APPs fragment formation and the activity of -secretase activity, which activates a non-amyloidogenic pathway in APP processing and excludes the formation of A (Peng et al., 2010). -Secretase inhibitors Based on efforts to discover compounds that modulate the production of A, some natural products have been reported to exert its neuroprotection by inhibiting the amyloidogenic pathway. For example, five secretase inhibitors were isolated from the root extract of Angelica dahurica (Fisch.) Benth. Et Hooker

(Umbelliferae), which is a traditional folk remedy used in Korea to treat headache, bleeding and menstrual discomfort. -Secretase inhibitors isolated from A. dahurica roots were types of furanocoumarins (Fig. 3) including isoimperatorin (6), imperatorin (7), (+)-oxypeucedanin (8), (+)-bakangelicol (9) and (+)-byakangelicin (10) (Marumoto and Miyazawa, 2010). Owing to their low molecular weight, these compounds can easily cross the blood-brain-barrier (BBB) and reach the brain. Protoberberine alkaloids from Coptis chinensis Franch. (Ranunculaceae), epiberberine (11) and groenlandicine (12) (Fig. 3), exert significant inhibitory activity against -secretase with IC50 values of 8.55 and 19.68 M (Jung et al., 2009). In particular, groenlandicine not only decreases the production of A by inhibiting -secretase, but can also have potent inhibitory effects on AChE and reactive oxygen species (ROS). In addition, an extract of Polygala tenuifolia Wild. (Polygalaceae) is commonly used as a traditional Chinese medicine to treat memory loss (Lv et al., 2009). An extract of P. tenuifolia was reported to alleviate scopolamine-induced cognitive impairment in rats (Park et al., 2002). Efforts to determine the major constituents responsible for the beneficial effects on memory loss allowed the isolation of the final product, tenuifolin (Lv et al., 2009). Tenuigenin is another active constituent in the root extract of P. tenuifolia (Jia et al., 2004). Both compounds have beneficial effects on AD by reducing the A burden that acts by inhibiting the -secretase activity thereby decreasing the A production. Recently resveratrol derivatives were reported to reduce the activity of -secretase, in spite of resveratrol itself does not demonstrate any related activity (Fig. 3). A new resveratrol dimer, (+)-vitisinol E and four known resveratrol oligomers, (+)-epsilon-viniferin (13), (+)-ampelopsin A (14), (+)-vitisin A (15) and (-)vitisin B (16), isolated from Vitis vinifera L. (Vitaceae), the common grape vine, exhibited strong inhibition on the -secretase activity in a dose-dependent manner (Choi et al., 2009). In addition, trans/cis-resveratrol mixture, oxyresveratrol (17), cis-scirpusin A (18) and veraphenol (19), which were isolated from the rhizomes of Smilax china L. (Smilaceae), showed potent inhibitory activity against -secretase (Jeon et al., 2007). Isoflavones including neocorylin, bakuchiol, bavachromene, isobavachromene, bavachalcone, 7,8-dihydro8-(4-hydrophenyl)-2,2-dimethyl-2-H,6-H-[1,2-B:5,4-B'] dipyran-6-one, isolated from Psoralea corylifolia L. (Fabaceae) were also strong inhibitors of -secretase activity (Choi et al., 2008b). In addition, luteolin and rosmarinic acid was identified as the active principles

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Fig. 3. Structures of -secretase inhibitors

of -secretase inhibition from Perilla frutescens var. acuta (Laminaceae) (Choi et al., 2008a).

Catechins primarily included in green tea are flavonoids that exert a range of pharmacological activi-

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ties. In particular, the neuroprotective effects with strong antioxidant and anti-inflammatory properties make catechins attractive compounds (Zaveri, 2006). Furthermore, an improvement in learning and memory by the catechins in green tea suggest promising roles in treating neurodegenerative disorders (Lin et al., 2007). (-)-Epicatechin gallate (20), (-)-epigallocatechin gallate (21), (-)-gallocatechin gallate (22), (-)-catechin gallate (23), (-)-gallocatechin (24), and (-)-epigallocatechin (25) (Fig. 3) inhibited -secretase with IC50 < 6 M, whereas IC50 values of (+)-catechin, (-)-catechin, (+)-epicatechin, and (-)-epicatechin in -secretase inhibition were 10 times higher. This suggests that the pyrogallol moiety on C-2 and/or C-3 of catechin is essential for the strong -secretase inhibitory activity (Jeon et al., 2003). -Secretase inhibitors The inhibition of -secretase activity reduces the A burden and is another approach for decreasing the AD-like pathology. Several potent -secretase inhibitors including N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT, 26), N2[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin7-yl]-l-alaninamide (LY411575, 27), and 2-[(1R)-1-[[(4chlorophenyl)sulfonyl](2,5-difluorophenyl)amino]ethyl]5-fluorobenzenepropanoic acid (BMS-299897, 28) (Fig. 4) is beneficial in AD by reducing the A burden in mouse brains (Anderson et al., 2005; Dovey et al., 2001; Lanz et al., 2004). However, the side effects of secretase inhibitors, such as an impairment of lymphocyte development and intrathymic differentiation and intestinal cell differentiation due to the concomitant inhibition of Notch processing pathways, has limited their therapeutic utility for AD. Therefore, search for compounds that inhibit -secretase, but not the Notch processing pathway can be undertaken and developed as anti-AD agents. Cyclohexenone and two aryl groups arranged on a core six-membered ring, an intermediate in synthesis of natural products displayed significant inhibitory effects on -secretase (Takahashi et al., 2006).

Fig. 4. Structures of -secretase inhibitors

Inhibitors of A oligomer formation (aggregation) The deposition of A in the form of SPs is a pathological hallmark of AD. Once A is secreted from APP by the sequential cleavage of - and -secretases, A soluble monomer aggregates and forms a random coil or -helix conformation. Then, A aggregates undergo conformational changes to a pleated -sheet, which is the mature form of A fibril commonly seen in SPs of

AD. A can take any form, ranging from monomers to an array of aggregates including dimmers, oligomers, protofibrils, diffuse plaques and fibrillar deposits (Barrow and Zagorski, 1991; Tierney et al., 1988). Previously, mature A fibrils were considered to be the major neurotoxic form of A. However, recent studies suggest that the soluble, oligomeric form of A is more toxic to neurons than the mature fibrils, and induces synaptic deterioration and neurodegeneration (Selkoe, 2002; Wirths et al., 2004). The severity of AD correlates well with the cerebral concentration of soluble oligomeric A, but not the mature insoluble fibrillar A (Lesne and Kotilinek, 2005). Therefore, in addition to the prevention of A production by modulating the -, -, or -secretase activities, the inhibition of A aggregation and destabilization of pre-formed A aggregates are also attractive therapeutic targets as anti-AD agents. One example of A oligomer inhibitor is 1,2,3,4,6penta-O-galloyl--D-glucopyranose (29) (Fig. 5) isolated from Paeonia suffruticosa Andrews (Paeoniaceae)

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Fig. 5. Structures of A aggregation inhibitors

(Fujiwara et al., 2009). Previously, P. suffruticosa was used as an anti-pyretic and anti-inflammatory (Chou, 2003; Lin et al., 1999). Paeonol, a major component of P. suffruticosa reduced the cerebral infarction in ischemia-reperfusion-injured rats (Hsieh et al., 2006). On the other hand, 1,2,3,4,6-penta-O-galloyl--D-glucopyranose, a high molecular weight tannin-type polyphenols, is the constituent responsible for inhibiting the formation of A aggregates (Fujiwara et al., 2009). 1,2,3,4,6-Penta-O-galloyl--D-glucopyranose inhibited the aggregation of A in vitro, and treatment of Tg2576 mice with 1,2,3,4,6-penta-O-galloyl--D-glucopyranose ameliorated the A-induced memory deficits and AD-like pathology in vivo. Like extracts of P. suffruticosa, polyphenols included in wine have been reported to reduce the risk of AD (Letenneur et al., 1993; Orgogozo et al., 1997). Tannins, polyphenols and flavonoids are neuroprotective by reducing oxidative stress in vivo and in vitro (Bastianetto et al., 2000b; Virgili and Contestabile, 2000). In particular, tannic acid was effective in inhibiting the formation of A aggregates and destabilizing the pre-formed A in a dose-dependent manner, even though the precise mechanisms of tannic acid on the inhibition of A oligomer formation were not fully

elucidated (Ono et al., 2004a). In addition, extracts of Uncaria rhynchophylla Miq. (Rubiaceae) were reported to be beneficial for AD. The extract of U. rhynchophylla reduced the formation of A aggregates in a concentration-dependent manner according to the thioflavin T binding method. Furthermore, fibrils or aggregates of A were dissociated by a treatment with U. rhynchophylla extract, indicating that U. rhynchophylla extract de-stabilizes A aggregates (Fujiwara et al., 2006). The major constituents including oxindole and indole alkaloids such as corynoxeine (30), hirsutine (31) and hirsuteine (32) (Fig. 5), were identified as anti-A aggregating principles from extracts of U. rhynchophylla. These compounds were also reported to be neuroprotective and act by inhibiting glutamate-induced neurotoxicity in cerebellar granule cells (Shimada et al., 1999). Curcumin (33) is a well-known natural product with a beneficial effect on AD. Curcumin is a major constituent in yellow curry spice turmeric (Curcuma longa L., Zingiberaceae), which is a traditional herbal medicine commonly used in India (Kelloff et al., 2000). The low incidence of AD in India compared to other countries has stimulated many studies on the effects of turmeric against AD (Ganguli et al., 2000). As a

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result, a variety of neuroprotective effects of curcumin have been reported. Curcumin is a strong antioxidant, and effectively scavenges free radicals and protects cells from oxidative damage in vitro cell culture studies (Sreejayan and Rao, 1997; Zhao et al., 1989). In addition, curcumin also has a strong antioxidant effect in Tg2576 mice (Lim et al., 2001). Curcumin was reported to inhibit the formation of A fibrils and destabilize the pre-formed fibrillar A in a dose-dependent manner in vitro (Ono et al., 2004b). Recent reports have indicated that a standardized turmeric extract is available with a range of chemical profiles that includes four curcuminoids, namely curcumin (33), demethoxycurcumin (34), bisdemethoxycurcumin (35) and tetrahydrocurcumin (36) (Fig. 5). The optimized extract of curcuminoids efficiently inhibited the aggregation of A with IC50 values < 5 g/mL (Shytle et al., 2009). Gupta and his colleagues have reported that garlic extract also exhibited inhibitory activity against A oligomerization (Gupta et al., 2009). The aqueous extract of garlic, either in fresh or boiled form reduced the formation of A fibrils in a dose- and time-dependent manner. The garlic extract also destabilized the preformed A fibrils with maximum effect observed after incubation for 2 or 3 days. This suggests that the inhibitory effect of a garlic extract on A oligomer formation is not through any enzyme reaction. Nevertheless, the consumption of garlic can be beneficial for AD.

Inhibitors of A-induced neurotoxicity Aggregated A (A oligomers) is one of the major causes of AD, which induces neurotoxicity, synaptic dysfunction, synaptic loss, eventually leading to neuronal death. Although the precise mechanism(s) of A-induced neurotoxicity is unclear, several possible mechanisms by which A mediates its neurotoxicity have been proposed; one of them being oxidative stress induced by A. Observations of increased oxidative damage to proteins, DNA and lipids in the postmortem tissue of the brains of AD patients suggest that oxidative stress is an important process that accelerated by A (Ansari and Scheff, 2010). In addition, it was reported that A increases the production of ROS and impairs the antioxidant defense system in a number of model systems (Abramov et al., 2003; Benzi and Moretti, 1995). Another neurotoxic mechanism exhibited by A is the disturbance in calcium homeostasis. A appears to induce the influx of Ca2+ from outside the cells into the cytoplasm. Ca2+ overload in the cytoplasm then triggers neurotoxicity by enhancing the release of glutamate, eventually leading to excitotoxicity (Rovira et al., 2002). In addition, neuro-

inflammation is considered one of the possible neurotoxic mechanisms induced by A (Cummings et al., 1998; Klein et al., 2001; Pike et al., 1997; Smith et al., 2006). Therefore, inhibition of A-induced neurotoxicity would be a good therapeutic strategy in the search and development of agents against AD. Ginkgo biloba L. (Ginkgoaceae) is a well-known natural product with an anti-AD effect. The extract of G. biloba green leaves (EGb761) contains 24% flavonoids (mainly flavonol-O-glycosides), 6% terpenoids (gingolides A, B, C, M, J and bilobalide) and 5-10% organic acids (Drieu, 1986). Among the constituents, flavonoids have an antioxidant effect against hypoxia and ischemia (Oberpichler et al., 1988; Szabo et al., 1997). In addition, EGb761 is beneficial in MCI in the elderly population (Rai et al., 1991). Furthermore, in cultured hippocampal neurons, EGb761 blocks and rescues neurons from A-induced toxicity and cell death by attenuating the accumulation of ROS and apoptosis (Bastianetto et al., 2000a). The neuroprotective effects of ginsenosides (Fig. 6), steroid glycosides found exclusively in the plant genus Panax, against A has been reported. Ginsenoside Rb1 (37) protects cultured cortical neurons from Ainduced toxicity through an antioxidant pathway by reducing the levels of lipid peroxidation and antioxidant enzymes such as superoxide dismutase (SOD) (Qian et al., 2009). In addition, ginsenoside Rg2 (38) also attenuates the glutamate-induced neurotoxic effects in PC12 cells through the antioxidant and antiapoptotic pathways (Li et al., 2007). The survival of PC12 cells were increased by treating ginsenoside Re (39) against serum-free medium and A (Ji et al., 2006), suggesting various ginsenosides have neuroprotective effects against neurotoxic compounds. In addition, various natural products have been reported to protect neuronal cells from A-induced toxicity (Summarized in Table II). Flavonoids, such as icariin and baicalein, were reported to protect neurons from A-induced toxicity. Triterpene-type ginkgolide B, diterpene-type isodojaponin D and isorosmanol are compounds classified as terpenoids that have an antiA effect. Lignans such as 4-O-methylhonokiol, lignins such as salvianolic acid B, and alkaloids such as (-)clausenamide are also neuroprotective against A. In addition, other types of compounds including curcumin, hyperforin, and dactylorhin B exhibit their protective effects on neuronal cells against A. Specific classes of compounds cannot be considered as neuroprotective principles against A primarily because a variety of natural products exhibit protective effects against A. Therefore, it is hard to predict the type of compound that is identified from an effec-

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Fig. 6. Structures of inhibitors against A-induced neurotoxicity Table II. A range of natural products protecting neuronal cells against A-induced toxicity Class of compound Compound name Icariin Flavonoid Quercetin 4,5-Dihydroxy-6,8-dimethyl7-methoxyflavanone Ginkgolide B Terpenoid Isodojaponin D Isorosmanol Lignan Lignin Alkaloid Others 4-O-Methylhonokiol Sesaminol glucoside Salvianolic acid B (-) Clausenamide Curcumin Hyperforin Dactylorhin B Origin Epimedium brevicornum Maxim (Berberidacear) Ginkgo biloba L. (Ginkgoaceae) Callistemon lanceolatus DC. (Myrtaceae) Ginkgo biloba L. (Ginkgoaceae) Isodon japonicas (Burm.) Hara (Labiatae) Salvia officinalis L. (Labiatae) Sesamum indicum L. (Pedaliaceae) Salvia miltiorrhiza Bunge (Labiatae) Clausena lansium (Wampi) (Rutaceae) Curcuma longa L. (Zingiberaceae) Hypericum perforatum L. (Hypericaceae) Coeloglossum viride L. (Orchidaceae) References Sha et al., 2009 Li et al., 2010 Shi et al., 2009 Park et al., 2010 Shi et al., 2009 Lim et al., 2010 Park, 2009 Um et al., 2009 Lin et al., 2006 Durairajan et al., 2008 Zhang et al., 2007 Park et al., 2008 Dinamarca et al., 2006 Zhang et al., 2006

Magnolia officinalis Rehd. Et Wils (Magnoliaceae) Lee et al., 2010

tive crude extracts of natural products against A.

Inhibitors of A-induced neuroinflammation Microglia are resident immune cells that function as the first and main active immune defense in CNS. Upon activation, they become large and produce a

range of inflammatory neurotoxic mediators, such as BDNF and nerve growth factor (NGF), as well as neurotoxic factors including pro-inflammatory cytokines, nitric oxide (NO), prostaglandin E2 (PGE2) and ROS (Hanisch, 2002; Minghetti and Levi, 1998) to fight off an infection. However, prolonged over-activation of

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microglia can cause chronic neuroinflammation due to the increased production of neurotoxic pro-inflammatory mediators, eventually leading to neuronal death (Block and Hong, 2005; Rojo et al., 2008; Zipp and Aktas, 2006). This phenomenon is commonly observed in several neurodegenerative diseases, including AD, Parkinsons disease, multiple sclerosis and cerebral ischemia (Drew et al., 2005; Gonzalez-Scarano and Baltuch, 1999). Therefore, anti-inflammatory therapy against the microglial activation consequent suppression in the production of neurotoxic pro-inflammatory mediators is a potentially beneficial approach in attenuating the progression of neurodegenerative diseases (Block et al., 2007) including AD. Ginseng, the root of Panax ginseng C. A. Meyer (Araliaceae), is the most widely used herbal medicine in the world, particularly in Asian countries (Blumenthal, 2001). Ginseng is considered to be effective in the prevention and treatment of a wide range of diseases including diabetes, allergy, hypertension and cancer (Radad et al., 2006). Among the many chemical components in ginseng, saponin ginsenosides are the compounds most responsible for the biological activities shown by ginseng. Several studies have reported that ginsenosides have beneficial effects on the CNS. For example, ginsenosides Rb1 and Rg1 induced neuritic outgrowth and were neuroprotective in dopaminergic neurons (Rudakewich et al., 2001). In addition, ginsenosides reduced ischemic brain damage in rats (Park et al., 2004; Tian et al., 2005), and improved the amnesia induced by A in rats (Wang et al., 2006a). Recently, ginseng saponins were reported to inhibit the activation of microglial cells and subsequently reduce neuronal cell death. This effect was mediated by the anti-inflammatory effects of ginsenosides, primarily by suppressing the activity of NF-B and MAP kinase followed by a decrease in inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines (Park et al., 2009). The overall beneficial effects of ginseng against neurodegenerative diseases indicate that ginseng will benefit in the treatment of AD. In addition of curcumins neuroprotective property mediated by inhibiting the production of A, enhancing the formation of -secretase-cleaved-APPs fragments and destabilizing the pre-formed A aggregates, it also displays non-amyloidogenic effects. Curcumin reduces the release of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF- (Jin et al., 2007), attenuates NO production and decreases the expression of COX-2. The anti-inflammatory properties of curcumin are exerted mainly by suppression of the NF-B signaling pathway (Kang et al., 2004). Co-culturing of neuronal cells with microglia indicated that the in-

flammatory conditions induced by microglial activation are the main target for curcumin by which they exert their neuroprotective effects against dopamineinduced neuronal death (Lee et al., 2007). Flavonoids, a group of phenolic compounds with a plant origin, have also been reported to have an antiinflammatory effect on neuronal cells. One example is wogonin (5,7-dihydroxy-8-methoxyflavone) isolated from the root of Scutellaria baicalensis Georgi (Apiaceae). A variety of biological activities of wogonin have been reported including anti-inflammatory effects in macrophages, human endothelial cells, and in the skin of mice (Chang et al., 2001; Park et al., 2001; Wakabayashi, 1999). The anti-inflammatory effect of wogonin on the CNS is well documented. Wogonin inhibited the production of NO and the expression of iNOS in cultured rat astrocytes (Kim et al., 2001). Wogonin inhibited the inflammatory activation of cultured microglial cells as well as demonstrated in in vivo experimental brain injury models including transient global ischemia and kainite-induced excitotoxic injury. The administration of wogonin to in vivo animal models protected the hippocampal neurons from ischemia and excitotoxic injury, and was accompanied by a decrease in microglial activation (Lee et al., 2003). These reports suggest that wogonin is a valuable compound with proven beneficial effect against AD. Another example of natural products with anti-inflammatory properties is baicalein (5,6,7-trihydroxyflavone) derived from the root of S. baicalensis. Baicalein exerts its anti-inflammatory effects in mouse macrophages and cultured human umbilical vein endothelial cells (Kimura et al., 2001; Wakabayashi, 1999). Studies have indicated that baicalein protects dopamineric neurons against lipopolysaccharide-induced injury by attenuating the microglial activation (Li et al., 2005). The decrease in microglial activation was accompanied by the down-regulation of TNF-, NO, superoxide and free radical formation (Suk et al., 2003). Tripterygium wilfordii Hook F (Celastraceae) is an ancient traditional Chinese medicine that has been used to treat joint pain and inflammation (Brinker et al., 2007). Triptolide, an active component from the extract of T. wilfordii, was identified as a major principle for its anti-inflammatory and immunosuppressive properties (Qiu and Kao, 2003). In addition, triptolide inhibited the dopaminergic neuronal damage induced by inflammation (Zhou et al., 2005). The mechanism of triptolides biological action in the protection against inflammation-mediated damage involved the signaling of the p38-NF-B-COX-2-PGE2 and JNK-PGE2 pathways (Gong et al., 2008).

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Inhibitors of acetylcholinesterase (AChE) As the cerebral cortex displays considerable damage in AD, a shortage of neurotransmitters, particularly ACh, in the synapses is strongly co-related with the symptoms of AD, and recovery of ACh has been shown to be beneficial in reducing AD-related symptoms, such as short-term memory loss (Francis et al., 1999). Therefore, tacrine, an inhibitor of the enzyme for the degradation of ACh, was the first FDA approved AChE inhibitor to be used as an anti-AD agent. Since then, efforts are directed towards discovering other AChE inhibitors from natural sources. The first success was huperzine A (40) (Fig. 7), a sesquiterpene alkaloid found in the plant firmoss Huperzia serrata (Thunb.) Trevis (Lycopodiaceae), which is a traditional Chinese medicine used widely to treat contusions, strains and schizophrenia. The active principle in H. serrata for improving memory is huperzine A, which inhibits the enzyme AChE and eventually increases the levels of ACh in the synapses (Ortega et al., 2004). In clinical studies conducted in China, huperzine A is known to enhance the memory, cognitive skills, and daily life abilities of AD patients (Wang et al., 2006b). In addition to the inhibitory effect on AChE, huperzine A enhanced the secretion of -secretase-cleavedAPPs fragments, suggesting an enhancement of the non-amyloidogenic pathway in terms of APP processing (Yan et al., 2007). Huperzine A is also known to act as a strong antioxidant by enhancing the activities of the antioxidant enzymes including glutathione

peroxide reductase, SOD and catalase, and suppressing the levels of lipid peroxidation (Xiao et al., 2000). Other than the antioxidant effect, the anti-apoptotic effects of huperzine A contributes to its neuroprotective effects against A by up-regulating the levels of Bcl-2 and down-regulating the levels of Bax and P53 (Wang et al., 2001). Galantamine (41) (Fig. 7) is an example of a natural product-derived AChE inhibitor that has been approved by FDA as an anti-AD medication. Galantamine is an alkaloid obtained from the bulbs and flowers of snowdrop Galanthus woronowii Losinsk. (Amaryllidaceae). This plant has been used as a medicine in the Soviet Union long since the 1950s to treat nerve pain and neural deformities similar to poliomyelitis and the bioactive principle of G. woronowii was identified accidently as galantamine (Marco and do Carmo Carreiras, 2006). In addition to its uses in anesthesiology, galantamine has been tested on AD patients, and showed positive effects on the galantamine on memory tests in some patients by acting as a longlasting, selective, reversible and competitive AChE inhibitor (reviewed at Sramek et al., 2000). Galantamine is a good example of a natural product substituting for other synthetic drugs for the treatment of AD (Marco and do Carmo Carreiras, 2006). Juliflorine (42) (Fig. 7) was originally isolated Prosopis juliflora (Sw.) DC. (Fabaceae) as an antimicrobial alkaloid against Gram positive bacteria (Ahmad et al., 1986). Since then, Choudhary and his

Fig. 7. Structures of AChE inhibitors

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colleagues reported a new biological activity of juliflorine as an inhibitor of AChE and butyrylcholinesterase enzymes (Choudhary et al., 2005b). Withania somnifera (L.) Dunal (Solanaceae) (commonly known as Ashwagandha) is an important traditional medicine as an ingredient in Ayurvedic medicine and nutraceutical supplements. Withanolides, C28-steroidal lactone triterpenoids, isolated from W. somnifera, inhibited AChE (Choudhary et al., 2005a). In addition, withanolide A (43) (Fig. 7) induced neuritic regeneration, neurite outgrowth as well as reconstruction of the pre- and post-synapses in cultured rat cortical neurons against A-induced toxicity (Kuboyama et al., 2005).

CONCLUSIONS
This review discussed some natural products used for the treatment of AD or potential anti-AD properties. A good example of natural product-derived compounds to reach a worldwide use as an anti-AD agent is galantamine. Galantamine is the first FDA-approved natural product that inhibits AChE and alleviates AD-related symptoms, such as memory loss. Several natural products are under evaluation in various phases of clinical trials to prove their beneficial effects as antiAD agents. For example, curcumin, an active component of turmeric, has a wide range of beneficial properties including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic effects. In addition to all these properties, curcumin benefits AD patients by inhibiting the production of A, destabilizing the preformed A aggregates, and attenuating A-induced neuroinflammation, thus revealing its promise as a therapeutic agent against AD. Curcumin is currently under phase II clinical trials for moderate to severe AD. Resveratrol, stilbene-type polyphenols derived from wine and many plants, is a famous natural product with a wide range of biological activities including anti-cancer, anti-inflammatory and beneficial cardiovascular effects. Recently, it was reported that moderate consumption of red wine can reduce the risk of AD by virtue of resveratrol. The beneficial effects of resveratrol against AD are believed to occur through a decrease in the A burden in the brain and a reduction of the oxidative stress induced by A. Based on these promising therapeutic benefits, resveratrol is currently under Phase III clinical studies to determine the effects of a resveratrol supplement in mild-tomoderate AD. EGCG, the popular polyphenols from green tea, is an effective neuroprotective compound inferred from

numerous cell- and animal-based studies. These effects are due to its well-known antioxidant effects, downregulation of the genes regulating programmed cell death, and modulation of the mitochondrial functions. In particular, EGCG reduced the levels of the toxic A through activation of the non-amyloidogenic pathway by inducing -secretase and preventing the aggregation of A to the toxic oligomeric form by direct binding of the unfolded proteins. These beneficial effects of EGCG against an AD-like pathology have led to EGCG being used in a Phase II clinical study to evaluate the efficacy of EGCG in the early stages of AD. Despite the presence of some compounds under developmental stages of clinical trials awaiting their launch as therapeutic agents for AD, most of the natural product-derived neuroprotective compounds still remain on the bench-top serving as an example of traditional uses of plants or a provision of their partial biological activities. Although neuroprotective compounds derived from natural sources are attractive therapeutic alternatives in the treatment of AD, the lack of statistically significant clinical efficacy is a major problem haunting the development of natural products to clinical pharmaceuticals. Many reports regarding the neuroprotective effects of natural products are based mostly on in vitro cell-based studies. In vitro results should be confirmed by in vivo animal studies to determine their biological activities as antiAD agents. It is unclear if bioactive compounds reach the brain in sufficient concentrations and in a biologically active form to exert their beneficial effects. In addition, precise targeting or the establishment of more specific targets is important for discovering lead compounds. Furthermore, to move on to in vivo and clinical studies, obtaining the active compounds in large quantities is another challenge with the development of natural products as therapeutic agents. In addition, as far as AD is concerned, a wider range of targets that are associated with the pathology of AD should be considered as molecular targets to discover anti-AD agents. AChE inhibitors can help alleviate the cognitive symptoms of AD patients, but they neither halt nor delay the disease progression. Therefore, a search for effective compounds that is directed against A production, A oligomerization, A-induced neurotoxicity and A-induced inflammation or activation of microglial cells is expected to provide alternative attractive targets for the discovery of natural therapeutic agents against AD.

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