Neuroprotective role of herbal alternatives in circumventing Alzheimer’s disease through multi-targeting approach - a review

ABSTRACT

Alzheimer’s disease (AD) is a common form of dementia affecting the elderly worldwide. It is a multifactorial neurodegenerative disorder with no known preventive therapy. Many of the drugs used in the treatment of AD, such as galantamine, rivastigmine, and donepezil, have unpleasant side effects, and hence physicians are keen to find alternatives. Research has shown that plants and their phytochemicals can alleviate AD. These plant products can act through various modes, such as inhibition of amyloid β, acetylcholine, and γ-secretase, modulation of antioxidants, and α-secretase activation, which are known to involve in the improvement of brain functions. A recent approach that has garnered the attention of many researchers in designing a drug against AD is the multi-target-directed ligand (MTDL), wherein the same molecule act on multiple targets. Many studies have reported the potential of herbs to act on multiple targets and display biological properties. The current review summarizes the ongoing evidence on the use of herbs and their derived bioactive molecules in the treatment of AD and in relieving disease-associated pathological events. Currently available plant-derived MTDLs for the treatment or slowing down of the progression of AD are also discussed.

KEYWORDS:

• Alzheimer’s disease
• herbs
• multi-target-directed ligands
• acetylcholinesterase
• natural products

Introduction

Alzheimer’s disease (AD) is an irreversible, chronic neurodegenerative disorder characterized by deterioration of cognitive functions and behavioral disturbances [1]. Globally, AD is the most common cause of dementia, affecting approximately 46.8 million people and expected to increase up to 131.5 million by 2050 [2]. The probability of AD aggressively increases with age, more particularly after the age of 65. Thus, age is the primary risk factor for AD development [3]. AD developed after 65 years of age is referred to as ‘sporadic’ (or late-onset), whereas AD developed before 65 is classified as ‘familial’ (or early-onset). Several complex pathogenic pathways are involved in the progression and development of the disease, including plaque formation, inflammatory cascade, oxidative stress, and cholinergic deficit [4]. These cognitive deficits lead to memory-related clinical symptoms, such as loss of episodic and newly learned memories [5] .

Acetylcholine- and glutamate-producing neurons are known to be damaged during AD, thereby affecting the synapses associated with them. This is in agreement with the early cognitive symptoms observed in AD [6]. The main factor for the degeneration of neurons is due to the increased activity of cholinesterases (ChEs), which leads to a decrease in acetylcholine (ACh) levels, which in turn stops the neuronal transmission signals [7]. Studies have also established that acetylcholinesterase (AChE) promote Aβ aggregation and a notable increase in the cortical levels of butyrylcholinesterase (BuChE), which is related to the formation of Aβ plaques and neurofibrillary tangles (NFTs) [8–10].

Many natural compounds are known to have neuroprotective effects during AD. A large family of plant isolates has proven to be a modality for treatment by their inhibitory effect on Aβ, cholinesterase, beta, and gamma secretases. Potent activation of alpha secretases by plant products also substantiates the neuroprotective effect. This review gives a detailed insight into the list of plants and their isolates as neuroprotective agents during AD.

Molecular mechanism of AD

The formation of NFTs and senile plaques are the main histopathological hallmarks of AD [11]. The senile plaques contain amyloid-beta (Aβ) peptide, which consists of 37–49 amino acid residues and are formed by the extracellular and transmembrane domains of amyloid precursor protein (APP) [12]. In plaques, the oligomers might be trapped in fibrillar aggregates. Oligomers may be the hazardous Aβ species that contribute to signaling pathway deregulation (Fyn, FAK, GSK3b, and CDK5), causing changes in cytoskeletal and synaptic proteins, as well as synaptic and neural damage [13] (Figure 1). During sporadic AD, APP is cleaved by gamma and beta secretases to form 4 kDa Aβ peptide. The cleavage product has a strong tendency to form aggregates. Aβ accumulation has been one of the major pathological events resulting from an imbalance between production and clearance [14]. The Aβ aggregation process initiates by self-assembling of Aβ monomers into low molecular weight oligomers, which in turn results in the formation of high molecular weight oligomers known as soluble aggregation intermediates. These further aggregate to form fibrils and accumulate in the brain [15,16]. It is believed that microglia and astrocytes then mount an inflammatory response to clear the amyloid aggregates, and this inflammation likely causes the destruction of adjacent neurons and their neurites.

Figure 1. Formation of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques contain amyloid beta (Aβ) peptide, which consists of 37–49 amino acid residues and are formed by the extracellular and transmembrane domains of amyloid precursor protein (APP). Oligomers may be the hazardous Aβ species that contribute to signaling pathway deregulation (Fyn, FAK, GSK3b, and CDK5), causing changes in cytoskeletal and synaptic proteins, as well as synaptic and neural damage.

Other than plaques, the presence of NFTs is considered another characteristic feature in the neuropathological event of AD [17]. These NFTs are insoluble twisted fibers formed by abnormal hyperphosphorylation of a microtubule-associated protein called ‘tau’. NTF in normal form serves as a microtubule-stabilizing protein and plays a role in intracellular (axonal and vesicular) transport [18]. NFT may interfere with the regular axonal transport of components necessary for proper neuronal function and survival, eventually causing neurons to die. In addition, Aβ is thought to trigger neuronal cell death via controlling apoptosis inducers, generating oxidative stress, and increasing free radical-mediated pathways[11].

Methodology

A detailed literature survey was performed using both offline and online resources. Data were mainly collected from various journal publishers, including Elsevier, Springer Nature, Taylor & Francis, Cambridge University Press, Oxford University Press, BioMed Central, and PLOS (Public Library of Science). The online databases such as Google Scholar, Pubget, Medline, PubMed, EMBASE, Mendeley, ScienceDirect, Scopus, and SpringerLink were also used to retrieve literature. The results were then cross-referred to generate the list of references (up to 2018) cited in this review. The Current review methodically summarizes the neuroprotective effects of phytochemicals in various models. Herbal extracts, bioactive constituents, and herbal formulations were included to provide references in the future.

Natural products in AD

Since time immemorial, natural products have been used as medicine for many ailments. Natural products are molecules with diverse functions and have been the source of most active constituents in medicine [19,20]. They are said to be the most successful basis of drug leads with lesser toxicity [21,22]. Natural products may be derived from plants, animals, or microorganisms. Most herbal medicines are complex and constitute many chemical components, which possess diverse biological and pharmacological activities.

Medicinal plants are nature’s gift that remains unexplored. The active component present in herbal medicine may serve as the basis for preparing synthetic drugs [22]. Plants can synthesize chemical compounds involved in preventing or curing various diseases, including memory dysfunction and age-related disorders. In modern medicine, plants occupy a very significant place as a source of raw material for synthetic drugs [23]

Cholinesterase inhibitors

The important etiological factor in the pathogenesis of memory deficit in AD is the impairment in cholinergic transmission [24]. The inhibition of AChE increases the levels of acetylcholine in the brain and thus improves the cholinergic functions in AD patients 25. Hence, cholinesterase inhibitors are currently used as standard drugs for treating AD. Tacrine was the first AChE inhibitor drug approved for AD treatment [26]. Later, many other AChE inhibitors such as rivastigmine, galantamine, and donepezil were also developed and approved by the FDA. These drugs alleviate the symptoms but are associated with side effects when used for an extended period [27]. As AD has reached a state of public health burden, the ever-increasing reports of side effects from these synthetic and hybrid drugs have driven the research for a novel and safe AchE inhibitors from plant sources.

Plants continue to be the unvaryingly abundant source of therapeutic drugs for AD treatment because of their AChE inhibitory activity. Several plant extracts of various solvents have been reported to show anticholinesterase activity. Aqueous and methanolic root extracts of Acacia nilotica and Withania somnifera possessed moderate anticholinesterase activity (IC50 values of 0.079 and 33.38 µg/ml, respectively) [28,29]. Much lesser inhibitory activity was observed in hydroethanolic seed extracts of Myristica fragrans, which showed 50% enzyme inhibition at a concentration range between 100 and 150 µg/mL [30]. Also, Pinus nigra was used to extracting essential oils possessing 94.4 µg/mL activity [31]. Similarly, different extracts of plants belonging to varied plant families have shown considerable cholinesterase inhibitory activity, which is listed in (Table 1).

Table 1. Plants with potential AChE inhibitory activity

Plant Family and Botanical Name	Type of Extract	Plant’s parts	References
Acanthaceae
Acanthus ebracteatus	MeOH	Aerial	[32]
Andrographis paniculata	H2O:EtOH	Aerial	[30]
Amaranthaceae
Salsola oppositifolia Salsola soda Salsola tragu	Alkaloids	Aerial	[33]
Amaryllidaceae
Crinum jagus	MeOH	Leaf	[34]
Crinum jagus Crinum bulbispermum Hippeastrum barbatum Hippeastrum puniceum Zephyranthes carinata	MeOH	Bulb	[35]
Crinum moorei	MeOH	Bulb	[36]
Sternbergia candida	MeOH, CHCl3	Root, Bulb	[37]
Anacardiaceae
Harpephyllum caffrum Sclerocarya birrea	MeOH, DCM	Leaf, Stem, bark	[Moy38]
Pistacia atlantica Pistacia lentiscos	H2O	Leaf	[39]
Semecarpus anacardium	MeOH	Seed, Bark	[29]
Spondias mombin	MeOH	Root, Bark	[34]
Araliaceae
Acanthopanax henryi	MeOH	Leaf	[40]
Eleutherococcus sessiliflorus Eleutherococcus gracilistylus Eleutherococcus senticosus Eleutherococcus setchuenensis Emmenopterys henryi Eurybia divaricatus	EtOH, CHCl3	Root	[41]
Asteraceae
Arnica chamissonis	MeOH, Hexane	Flower	[42]
Artemisia annua	EtOH	Leaf, twig	[43]
Chromolaena tequendamensis Schistocarpha sinforosi	MeOH	Whole plant	[44]
Pulicaria stephanocarpa	CHCl3	Leaf	[45]
Caprifoliaceae
Nardostachys jatamansi	Methanolic	Rhizome	[29]
Scabiosa arenaria	EtOH, Butanol	Fruit, stem, leaf	[46]
Chenopodiaceae
Atriplex laciniata	MeOH. CHCl3, H2O, Ethyacetate	Whole plant	[47]
Convolvulaceae
Evalvulus alsinoides	H2O:EtOH	Whole plant	[30]
Ipomoea asarifolia	MeOH	Leaf	[48]
Elaeocarpaceae
Aristotelia chilensis	H2O:EtOH	Leaf	[49]
Ericaceae
Cephalocroton socotranus	CHCl3	Bark	[45]
Euphorbia characias	H2O, EtOH	Leaf, stem	[50]
Jatropha gossypifolia	DCM, MeOH	Stem, bark roots	[51]
Rhododendron luteum Rhododendron ponticum	CHCl3:MeOH (1:1)	Whole plant	[52]
Euphorbiaceae
Alchornia laxiflora	MeOH	Leaf	[34]
Fabaceae
Acacia nilotica	H2O	Root	[28]
Acacia raddiana	H2O	Bark	[39]
Albizia adianthifolia	MeOH, Ethylacetate, CHCl3 fraction	Leaf	[53]
Albizia procera	MeOH	Bark	[32]
Cassia obtusifolia	EtOH	Seed	[54]
Genista tenera	EtOH	Aerial	[55]
Lathyrus cicero Lathyrus digitatus	MeOH	Aerial (Except seed)	[56]
Senna alata	EtOH	Leaf	[48]
Trigonella foenum-graecum	EtOH	Seed	[57]
Fumariaceae
Fumaria asepala Fumaria capreolata Fumaria cilicica Fumaria judiaca Fumaria kralikii Fumaria vailantii	CHCl3:MeOH (1:1)	Whole plant	[52]
Hypericaceae
Hypericum amblysepalum	MeOH	Flower, fruit, seed	[58]
Hypericum humifusum Hypericum perfoliatum	MeOH	Aerial	[59]
Lamiaceae
Cyclotrichium niveum	EtOH, DCM	Whole plant	[52]
Hyssopus officinials	Hexane	Whole plant	[42]
Leonurus sibiricus	MeOH	Aerial	[60]
Mentha longifolia, Mentha x piperita, Salvia officinalis Satureja montana, Teucrium arduini, Teucrium chamaedrys Teucriumpolium Thymus vulgaris Trifolium montanum	EtOH	Leaf Aerial Leaf Aerial Aerial Aerial Aerial Aerial Aerial	[61]
Mimosa pudica	MeOH	Whole	[32]
Pycnostachys reticulata	MeOH:EtOH (1:1)	Leaf	[62]
Salvia fruticose	DCM	Whole plant	[63]
Salvia miltiorrhiza	H2O, EOH	Root	[64]
Salvia officinalis	EtOH	Whole plant	[27]
Salvia tiliifolia	MeOH	Whole plant	[126]
Stachys guyoniana Mentha aquatica	MeOH, CHCl3, Butanol, Ethylacetate	Aerial	[65]
Leguminosae
Butea superba Cassia fistula	MeOH	Root, bark Root	[32]
Cassia obtusifolia	MeOH	Seed	[66]
Chamaecrista mimosoides	MeOH	Root	[126]
Liliaceae
Habranthus tubispathus Habranthus jamesonii	Alkaloid	Aerial	[67]
Lycopodiaceae
Huperzia squarrosa	EtOH fraction	Aerial	[68]
Menispermaceae
Stephania pierrei	EtOH	Tuber	[69]
Stephania suberosa	MeOH	Root	[32]
Tiliacora triandra	CHCl3:MeOH (1:1)	Root
Tinospora cordifolia	MeOH	Stem	[29]
Moraceae
Ficus religiosa	MeOH	Stem, bark	[29]
Morus alba	EtOH, MeOH, H2O	Aerial	[70]
Streblus asper	MeOH	Seed	[32]
Myristicaceae
Myristica fragrans	H2O:EtOH	Seed	[30]
Myrsinaceae
Embelia ribes	Methanolic	Root	[29]
Myrtaceae
Eugenia dysenterica	H2O	Leaf	[71]
Nymphaeaceae
Nelumbo nucifera	H2O:EtOH	Rhizome	[30]
Orchidaceae
Vanda roxburghii	Methanol	Root	[72]
Paeoniaceae
Paeonia lactiflora	H2O, EtOH	Root	[64]
Papaveraceae
Corydalis intermedia Corydalis solida	MeOH, H2O	Whole plant, Tuber	[73]
Pedaliaceae
Harpagophytum procumbens	MeOH	Hairy root	[74]
Pinaceae
Pinus halepensis	EtOH	Needle Twig	[75]
Pinus nigra	Essential oil	Needle	[31]
Poaceae
Cymbopogon schoenanthus	Hexane, DCM, EtOH, MeOH, H2O	Shoot	[76]
Polygalaceae
Polygala tenuifolia	H2O	Root	[27]
Olax subscropioidea Securidaca longipendunculata	H2O	Leaf	[77]
Polygonaceae
Rheum palmatum Fallopia multiflora	H2O, EtOH	Root, Rizhome	[64]
Ruprechtia apetala	EtOH	Aerial	[78]
Rosaceae
Crataegus pinnatifida	EPHF extract	Fruit	[79]
Rubus coreanus	EtOH	Whole plant	[80]
Rubiaceae
Paedaria linearis	MeOH	Whole plant	[32]
Sarcocephalus latifolius	EtOH	Bark	[81]
Rutaceae
Aegle marmelos	MeOH	Fruit pulp	[32]
Ruta graveolens	MeOH, Hexane	Whole plant	[42]
Sapotaceae
Mimusops elengi	MeOH	Flower	[32]
Scrophulariaceae
Bacopa Monniera	Ethanolic	Whole plant	[82]
Solanaceae
Withania somnifera	MeOH	Root	[29]
Tamaricaceae
Valerianaceae
Nardostachys jatamansi	H2O:EtOH, MeOH	Rhizome	[30]
Zingiberaceae
Kaempfera parviflora	EtOH	Rhizome	[69]

Alkaloids derived from various plant extracts show immense potential for AChE inhibitory activity. However, significantly few isolated compounds have been utilized for research and therapeutic purposes. Many isolated compounds from different classes of alkaloids have been considered and tabulated in (Table 2).

Table 2. Isolated compounds from plants with potential AChE inhibitory activity

Isolated compound	Classification	Plants	Family	References
Alkaloids
1-epi-malycorin A 1-epi-17S-hydroxymalycorin A 6α-hydroxyphlegmariurine A 2S,4 R-dihydroxyfawcettimine 16-hydroxylycodine	Lycopodium alkaloids	Phlegmariurus henryi	Lycopodiaceae	[83]
31-hydroxybuxatrienone Macowanioxazine 16a-hydroxymacowanitriene Macowanitriene Macowamine	Steroidal alkaloids	Buxus macowanii	Buxaceae	[84]
3-hydroxy-2,2,6-trimethyl- 3,4,5,6-tetrahydro-2 H-pyrano(3,2-c) quinoline-5-one, Ribalinine Methyl isoplatydesmine	Quinoline alkaloids	Skimmia laureola	Rutaceae	[Atta-ur 85]
7-O-angeloyllycopsamine N-oxide Echimidine N-oxide, Echimidine 7-O angeloylretronecine =	Pyrrolizidine alkaloids	Echium confusum	Boraginaceae	[39]
Berberine Palmatine	Isoquinoline alkaloids	Coptis Chinensis	Ranunculaceae	[27]
Columbamine Jatrorrhizine Coptisine Palmatine	Isoquinoline alkaloids	Coptis chinensis	Ranunculaceae	[86]
Coronaridine Voacangine Voacangine hydroxyindolenine Rupicoline	Indole alkaloids	Tabernaemontana australis	Apocynaceae	[87]
Dehydroevodiamine-	Quinazolinocarbolin	Evodia rutaecarpa	Rutaceae	[88]
Fumaranine Fumarostrejdine	Isoquinoline alkaloids	Fumaria officinalis	Papaveraceae	[89]
Geissospermine	Indole alkaloid	Geissospermum vellosii	Apocynaceae	[90]
Hookerianamide H and I	Steriodal alkaloids	Sarcococca hookeriana	Buxaceae	[91]
Isotalatazidine hydrate	Diterpenoid alkaloid	Delphinium denudatum	Ranunculaceae	[92]
Juliflorine	Piperidinum alkaloid	Prosopis juliflora	Papilionaceae	[93]
Kokusaginine Melineurine	Furoquinoline Alkaloids	Evodia lepta	Rutaceae	[94]
Lycorine	Pyrrolo(de)phenanthridine alkaloid	Narcissus pseudonarcissus	Amaryllidaceae	[95]
Mulberrofuran G Albanol B Kuwanon G Berberine	Benzyl isoquinoline alkaloids	Morus alba	Moraceae	[70]
Physostigmine	alkaloid	Physostigma venenosum	Fabaceae	[96]
Rauvolfine C 3-methyl-10,11-dimethoxy-6-methoxycarbonyl-β-carboline	Indole alkaloids	Rauvolfia reflexa	Apocynaceae	[97]
Salignenamides-C, E and F, Axillarine-C Saligcinnamide Vaganine-A 5,6-dehydrosarconidine 2-hydroxysalignarine-E Salignamine 2-hydroxysalignamine-E Epipachysamine-D Dictyophlebine Iso-N-formylchonemorphine Axillaridine-A	Steroidal alkaloids	Sarcococca saligna	Buxaceae	[91]
Strychnuxin	Pyrrole alkaloid	Strychnos nuxblanda	Loganiaceae	[98]
Taspine	Phenanthrene alkaloid	Magnolia x soulangiana	Magnoliaceae	[99]
Flavonoid
Agritannin Agriflavone Kaempferol-3- O-((S)-3-hydroxy-3-methylglutaryl (1→6))-β-D-glucoside-	Flavone	Agrimonia pilosa	Rosaceae	[100]
Catechin, quercetin	Flavonols	Eugenia dysenterica	Myrtaceae	[71]
Isorhamnetin Isorhamnetin-3-O-α-l-Rhamnopyranosyl-(1 → 6)-β-d-Galactopyranoside Pinitol Cyclomacroside D	Flavonol triglycoside	Astragalus armatus.	Fabaceae	[101]
Naringenin	Flavanone	Citrus junos	Rutaceae	[102]
α/β-glucoside-4-phenylacetate-6-(1-hydroxy-4-oxo-2,5-cyclohexadiene-1-acetate	Glucoside	Jacaranda oxyphylla	Bignoniaceae	[103]
Terpenoids
1,8-cineole and α-pinene-	Monoterpenes	Salvia lavandulaefolia	Labiatae	[27]
3β)-hopan-3-ol-28,22-olide	triterpenoid	Xylia xylocarpa	Fabaceae	[84]
Dihydrotanshinone Cryptotanshinone	Diterpenes	Salvia miltiorrhiza	Lamiaceaea	[104]
Scapaundulin C	Diterpenoid	Scapania undulata	Scapaniaceae	[105]
Trichinenlide U-X	Triterpenoids	Trichilia sinensis	Meliaceae	[83]
Ursolic acid	pentacyclic triterpenoid	Origanum majorana	Lamiaceae	[106]
Volvalerenal H-K Densispicnins C	Sesquiterpenoid	Valeriana officinallis	Valerianaceae	[107]
α-pinene, β-pinene, γ-terpinene	Monoterpenes	Centella asiatica	Umbelliferae	[108]
Limonoids
Dregeanin DM4 Rohituka 3 Trichilia lactone D5	Limonoids	Trichilia welwitschii	Meliaceae	[109]
Peptides
Aurentiamide acetate N-benzoylphenylalaninyl-N-Benzoylphenylalaninate	Peptide derivative	Cratylia mollis	Leguminosae	[110]
Phenolics
Honokiol	biphenols	Magnolia officinalis	Magnoliaceae	[111]
Steroids
Artemisinin Scopoletin Chrysosplenetin Eupatin 3-O-β-d-glucopyranoside	Sitosterol	Artemisia annua	Asteraceae	[43]
Sitoindosides	Steroid glycoside	Withania somnifera	Solanaceae	[27]

γ- and β-secretase inhibitors

Many plant extracts and their derived compounds are found to influence the Aβ production pathways, mainly by interacting with brain enzymes like β- and γ-secretases [112,113]. As explained earlier, both β- and γ-secretases are involved in the synthesis of Aβ. β-secretase cleaves the APP to form a transmembrane C-99 fragment with the N-terminus of the Aβ peptide (Figure 2) followed by the action of γ-secretase, which cleaves C-99 fragment in the transmembrane domain to make the C-terminus of Aβ [112].

Figure 2. β- and γ-secretases are involved in the synthesis of Aβ. β-secretase cleaves the APP to form transmembrane C-99 fragment with the N-terminus of the Aβ peptide. This is followed by the action of γ-secretase, which cleaves C-99 fragment in the transmembrane domain to make the C-terminus of Aβ.

In addition to β-APP processing, γ-secretase also plays a vital role in the cleavage of the Notch family of cell-surface receptors, a protein mainly required for transcriptional regulation during neuron development [114]. As a result, the use of γ-secretase inhibitors has provided insights into proteolytic activity and suggests that such inhibition might be a useful strategy for AD therapeutics [115]. A triterpene isolated from Actaea racemosa reduced the formation of Aβ toxicity through the modulation of γ-secretase activity. Thus, it suggests that the isolated compound may bind to γ-secretase APP complex, modulating the cleavage of APP and hence lowering the formation of Aβ peptides. 116,demonstrated that the use of green tea polyphenol epigallocatechin-3-gallate (EGCG) inhibited LPS-induced Aβ elevation levels through the suppression of LPS-induced β- and γ-secretase activities [116]. However, the inhibition of Notch protein by γ-Secretase inhibitors affects neuronal development, as Notch has multiple substrates that are involved in neuronal development [117]. Hence, β-secretase, also referred to as β-site APP cleaving enzyme 1 (BACE-1), a transmembrane aspartic protease secreted in almost all tissues but present in higher amounts in neurons of the brain [115], is considered as the most promising target for pharmaceutical research on AD, compared to γ-secretase.

α- secretase activators

α-secretase enzyme proteolytically cleaves the APP via the non-amyloidogenic pathway at L688 residue located within the Aβ sequence and thereby preventing the formation of Aβ (Figure 2). The first enzyme for α-secretase was proposed in 1998, when ADAM17, also known as tumor necrosis factor-converting enzyme (TACE), was reported to possess α-secretase activity [118]. Later, ADAM9 and ADAM10 were also shown to have α secretase activity [119]. These three proteins belong to the ADAM (a disintegrin and metalloprotease) family. It is reported that mutations in ADAM10 alter the processing of APP and lead to AD by increasing Aβ levels [120]. Thus, a promising yet underestimated approach to overcome AD would be, activating α-secretase processing of βAPP.

Moderate overexpression of ADAM10 in an APP mouse model showed a decreased level of Aβ, and prevented its accumulation. Such decreased levels of Aβ are found to alleviate cognitive deficits [121,122]. Various studies have corroborated that several drugs currently used in the treatment of AD promote α-secretase activity by activating associated signaling cascades. Thus, it has been considered as one of the best therapeutic approaches in AD [123–125].

Aβ inhibitors

Bioactivity-guided isolation has led to the discovery of novel bioactive compounds from plants, which are useful in preventing Aβ-induced neuronal cells [126]. In vitro assays were widely used to assess the activity of isolated compounds. It is observed that phenolic compounds, alkaloids, and glycosides comprise the major part of the isolated compounds with Aβ inhibitory activity. Their antioxidant activity and lipophilicity make it easy for them to cross the blood-brain barrier [126]. A list of compounds with Aβ inhibitory activity is provided in (Table 3 and 4).

Table 3. Plants with inhibitory activity against Aβ

Plants	Families	Type of extract	Models or assays	Key mechanism	References
Alpinia galanga	Zingiberaceae	CHCl3, Hexane, Ethyl acetate fractions	In vivo Swiss albino mice	Increased Free radical scavenging activity, Na^+/K^+ ATPase activity and exhibit AChE inhibition	[127]
Angelica gigas	Umbelliferae	EtOH	In vivo ICR mice	Inhibition of AChE and possesses rich antioxidant activity	[128]
Bacopa monnieri	Plantaginaceae	EtOH	In vitro Primary cortical neurons	Inhibition of amyloid peptide activated intracellular AChE activity and Regulation of neuronal transcription protein	[129]
Bambusae concretio	Gramineae	H2O	In vitro Cortical astrocyte cells	Attenuation of lipid peroxidation product and protection of antioxidant enzymes	[130]
Caesalpinia crista	Fabaceae	H2O	In vitro ThT and microscopic analysis	Inhibition of Aβ aggregation and disaggregation of preformed fibrils	[131]
Capsicum annuum	Solanaceae	MeOH	In vitro ThT, β secretase activity	Significantly inhibited β-secretase and unveil dis-aggregation of preformed Aβ40 fibrils	[132]
Centella asiatica	Apiaceae	H2O	In vitro MC65 and SH-SY5Y neuroblastoma cells	Prevented Aβ induced decreases in ATP and induced the expression of mitochondrial genes and proteins in both cell lines	[133]
Cinnamomum zeylanicum	Lauraceae	H2O	In vitro ThT, PC 12 cells In vivo 5XFAD mice	Inhibition of fibril formation and destabilization of pre-formed fibrils, reduction of Aβ deposition	[134]
Crocus sativus	Iridaceae	H2O:EtOH	In vitro ThT, DNA binding shift assay In vivo 5XFAD mice	Binding to the hydrophobic regions of the Aβ through the hydrophobic carotene backbone and inhibiting fibril formation Increased Aβ clearance across the BBB through up-regulation Pgp and LRP1, NEP, and up-regulation of the ApoE-clearance pathway	[135,136]
Ecklonia cava	Lessoniaceae	Butanol	In vitro Primary cortical neurons, HEK293 cells	Exhibit rich antioxidant activity, prevention of Aβ oligomer and fibril formation	[137]
Eleutherococcus senticosus	Araliaceae	Ethyl acetate, Butanol H2O fractions from the MeOH extract	In vitro Primary cortical neurons	Prevention of Aβ25–35 induced axonal atrophy	[138]
Ficus macrophylla	Leguminosae	EtOH, Ethylacetate, MeOH fraction,	In vitro swAPP-N2a cells	Inhibition of β-secretase and activation of insulin degrading enzyme	[139]
Ganoderma lucidum	Ganodermataceae	H2O	In vitro Primary cortical neurons	Reduction of Aβ-induced synaptotoxicity, inhibition of Aβ-induced DEVD cleavage activity and reduction of the phosphorylation of c-Jun and p38 MAP kinase and c-Jun n-terminal kinase	[140]
Ginkgo biloba	Ginkgoaceae	flavonoids and terpenoids extract (EGb 761)	In vitro Hippocampal primary cultured cells	Attenuation of Aβ25–35 induced apoptosis	[141]
Glycyrrhiza uralensis	Fabaceae	H2O	In vitro PC12 cells	Suppression of Aβ induced apoptosis and ROS generation	[11]
Grewia tiliaefolia	Tiliaceae	MeOH	In vitro ThT, microscopic analysis	Preventing the oligomerization of Aβ25–35	[142]
Houttuynia cordata	Saururaceae	H2O	In vitro Primary cortical neurons	Attenuation of Aβ25–35 induced elevation of intracellular ROS,calcium, caspase-3 activation and mitochondrial membrane disruption	[143]
Humulus japonicus	Cannabaceae	MeOH	In vivo Tg-APP/PS1 mice	Decreased the Aβ and neurofibrillary tangles and also decreased mRNA expression (TNF-α, IL-1β, IL-6) levels	[144]
Hypericum perforatum	Hypericaceae	H2O:EtOH (1:1) H2O	In vitro Microglial cell line BV2 In vivo AlCl3 induced rat	Attenuation of Aβ-induced ROS generation and membrane fluidity increase Decreased oxidative stress, Aβ accumulation and neuroinflammatory changes in rat hippocampal region.	[145,146]
Lycium barbarum	Solanaceae	Alkaline extract	In vitro Primary cortical neurons	Attenuation of caspase-3 activity triggered by Aβ and stimulation of the Akt survival pathway	[147]
Melissa officinalis	Magnoliaceae	EtOH	In vivo ICR mice	Inhibition of Aβ1–42 induced ROS generation and neuronal cell death	[148]
Monsonia angustifolia	Geraniaceae	EtOH	In vitro HeLa cells and In vivo in vivo Tg2576 mice	Reduced the level of insoluble Aβ42 in brain regions and increased memory function.	[149]
Paeonia suffruticosa	Paeoniaceae	EtOH, MeOH, H2O	In vitro ThT In vivo transgenic 2576 mice	Inhibition of fibril formation and destabilization of pre-formed fibrils, Inhibition of Aβ plaque formation	[150]
Piper nigrum	Piperaceae	MeOH	In vivo Aβ1–42 induced AD model	improves amyloid beta(1–42)-induced spatial memory impairment by inhibiting oxidative stress in the rat hippocampus	[151]
Pterocarpus erinaceus	Fabaceae	H2O	In vitro CHO-K1 cells	Inhibition of γ-secretase activity at the γ-site where Aβ is produced	[152]
Ptychopetalum olacoides	Olacaceae	EtOH	In vivo CF1 albino mice	inhibition of Aβ-induced cytotoxicity and AChE activity	[153]
Rhizoma. acori	Acoraceae	H2O	In vitro PC12 cells	Inhibition of cytotoxic action of Aβ1–40	[154]
Salvia sahendica	Lamiaceae	MeOH	In vivo Aβ micro injected rats	Decrease in levels of Ca2+/cAMP-response element binding protein, c-fos and peroxisome proliferator-activated receptor gamma coactivator-1α levels in Aβ-injected rats	[155]
Satureja bachtiarica	Lamiaceae	MeOH	In vivo Aβ microinjected rat model	Improved Aβ induced cognitive impairment and cholinergic loss and decreased oxidative stress	[156]
Schisandra chinensis	Schisandraceae	Hexane: EtOH (9:1)	In vivo ICR mice	Inhibition of AChE increasing levels of glutathione in cortex and hippocampus and reduction in the levels of β-secretase	[157]
Smilacis chinae	Liliaceae	MeOH	In vitro Rat cerebral cortical neurons	Blockage of (Ca2+)c increase, glutamate release, ROS generation and caspase-3 activation	[158]
Trigonella foenum-graecum	Fabaceae	Seed powder	In vivo AlCl3 induced rat model	Suppresses aluminium overload, Aβ accumulation, and apoptosis through activating Akt/GSK3β pathway	[159]
Uncaria rhynchophylla	Rubiaceae	H2O	In vitro ThT Microscopic Electrophoretic study	Inhibition of Aβ fibril formation	[160]
Zingiber officinale	Zingiberaceae	Seed	In vitro ThT and primary hippocampal neuron	Prevented the formation of oligomers and dis-aggregated the pre formed fibrils. Also, inhibited AChE activity and increased Aβ induced cell survival	[161]
Ziziphus mucronata Lannea schweinfurthii Terminalia sericea Crinum bulbispermum	Rhamnaceae Anacardiaceae Combretaceae Amaryllidaceae	EtOH	In vitro neuroblastoma SH-SY5Y cells	Attenuated the effects of Aβ induced neuronal cell death	[162]

Table 4. Natural Compounds with inhibitory activity against Aβ

Compounds	Plants and Family	Models/assays	Key mechanism	References
Alkaloid
Berberine	Coptis chinensis (Ranunculaceae)	In vivo TgCRND8 mice	N2a-SwedAPP cells regulation of the processing of amyloid precursor protein	[163]
Caffeine	Coffea arabica (Rubiaceae)	In vitro neuroblastoma 2a cells In vivo APP transgenic mice	Reduces levels of Aβ in neuroblastoma 2a cells stably expressing human Swedish mutant Prevents and reverses cognitive impairment in young and aged Swedish mutant APP transgenic mice	[95,164]
Dehydroevodiamine	Evodia rutaecarpa (Rutaceae)	Aβ1–42 infused rat model	Rescued Aβ induced neurotoxicity decreased ROS, and intracellular calcium levels	[88]
Huperzine A	Huperzia serrate (Lycopodiaceae)	In vivo Sprague Dawley rats	Inhibition of Aβ induced down regulation of APP secretion and protein kinase C	[165]
Nicotine	Nicotiana tabacum (Solanaceae)	In vivo mice model	Enhances cholinergic function, and it binds to Aβ and blocks its aggregation	[166]
Rhynchophylline Isorhynchophylline	Uncaria rhynchophylla (Rubiaceae)	In vitro PC12 cells	Rescue PC12 cells from cell death after Aβ challenge. Inhibits caspase-3, increases the ratio of Bcl-2/Bax protein expression, and stabilizes mitochondrial membrane potential. Also, reduction of Ca^2+ overload and tau protein hyperphosphorylation	[167,168]
Tetrandrine	Stephania tetrandra (Menispermaceae)	In vivo Sprague Dawley rats	Inhibition of NF-κB activity and downregulation of IL-1β and TNF-α expression	[169]
Vincamine	Vinca minor (Apocynaceae)	In vitro PC12 cells	Protects Aβ25–35 induced cell death via upregulation of SOD and activation of PI3K/Akt pathway	[170]
Z-ligustilide	Umbelifers (Apiaceae)	In vitro Aβ induced PC12 and SH-SY5Y human neuroblastoma cells	Protects against Aβ fibrils-induced neurotoxicity via inhibition of p38 and activation of PI3-K/Akt signaling pathways	[171]
Amino acids
L-Theanine	Camellia sinensis (Theaceae)	In vivo SIc:ICR mice	Suppression of extracellular signal-regulated kinase/p38 and NF-κB induced by Aβ1–42 and prevents lipid damage in the brain	[172]
Cannabinoid
Cannabidiol	Cannabis sativa (Cannabaceae)	In vitro PC12 cells	Attenuation of phosphorylated form of p38 MAP kinase and NF-κB activation	[173]
Carotenoids
Dimethylcrocetin	Crocus sativus (Iridaceae)	In vitro ThT, DNA binding shift assay	Inhibition of Aβ aggregation and fibrillogenesis	[135]
Fucoxanthin	Sargussum horneri (Sargassaceae)	In vitro ThT and microsopical studies In vivo Aβ1–42 microinjected mice	Effectively inhibited Aβ assembly. Reversed cognitive impairments through inhibiting oxidative stress, increasing BDNF expression and elevating cholinergic system	[174]
Flavonoid
3,4-Dihyroxybenzoic Acid-	Smilacis chinae (Smilacaceae)	In vitro Primary cortical neurons	Reduced increase in (Ca2+) and inhibition of glutamate release, caspase-3 activity and ROS generation	[175]
7- Demethylageconyflavone A, Tricin, Ageconyflavone A, Corylin, Nectandrin B, 4-Ketopinoresino-	Eragrostis ferruginea (Poaceae)	PC12 cells	Protects Aβ induced toxicity	[176]
Acerogenin A	Acer maximowiczianum (Sapindaceae)	In vitro HT22 cells	Prevents glutamate-induced oxidative damage. HO-1 induction through PI3K/Akt and Nrf2 pathways	[177]
Apigenin	Elsholtzia rugulosa (Lamiaceae)	In vitro APPsw cells	Attenuation of intracellular ROS generation, preserved mitochondrial function and regulation of apoptotic pathways	[178]
Biochanin A	Trifolium pretense (Fabaceae)	PC12 cells	Protective effect against Aβ25–35 and attenuated PC12 cell injury and apoptosis by preventing mitochondrial dysfunction. Also, estoration of Bcl-2/Bax and Bcl-xL/Bax ratio.	[179]
Caffeic acid	Solanum tuberosum (Solanaceae)	In vitro PC12 cells	Reduced levels of intracellular calcium and tau phosphorylation	[180]
Catechin	Hypericum perforatum (Hypericaceae)	In vitro Microglial cell line BV2, N11 cells	Reduction of Aβ induced ROS generation and increase of membrane fluidity	[146]
Chlorogenic acid		PC12 cells	Attenuates Aβ-induced neurotoxicity by reducing apoptotic effect and inhibiting calcium influx by Aβ	[181]
Curcumin	Curcuma longa (Zingiberaceae)	In vivo APPswe/PS1dE9dtg mice	Reduced the expressions of hippocampal Aβ40, Aβ42 and ADDLs in brains	[182]
Decursin	Angelica gigas (Apiaceae)	PC12 cells	Significantly inhibited Aβ25–35-induced cytotoxicity and apoptosis	[183]
Ellagic acid	Rubus idaeus (Rosaceae)	In vivo Aβ25–35 microinjected rats	Atenuated oxidative stress and modulation of NF-κB/Nrf2/TLR4 signaling pathway.	[184]
Emodin	Polygonum cuspidatum (Polygonaceae)	In vitro Cultured cortical neurons	Up regulation of B-cell lymphoma-2, activation of ER/P13 K/Akt pathway and inhibition of JNK1/2 phosphorylation	[83]
Epicatechin	Hypericum perforatum (Hypericaceae)	In vitro Microglial cell line BV2, N11 Cells	Inhibition of Aβ induced ROS generation and increase of membrane fluidity	[146]
Epigallocatechin-3- gallate	Camellia sinensis (Theaceae)	In vivo ICR mice	Attenuation of LPS induced β- and γ-secretase activity, expression of inflammatory proteins, inducible cyclooxygenase-2 and nitric oxide synthetase	[116]
Eugenol	Rhizoma acori (Araceae)	In vitro PC12 cells	Inhibition of Aβ induced Ca2+ intake	[154]
ɛ-Viniferin	Vitis vinifera (Vitaceae)	In vitro PC12 cells	ROS Scavenging activity and inhibition of Aβ fibrillization	[185]
Ferulic acid		PSAPP mouse model	Significantly decreased Aβ production and reduced amyloidogenic APP proteolysis. Also acts as β-secretase modulators.	[186]
Gallic acid	Sanguisorba officinalis (Rosaceae)	In vitro Primary cortical neurons	Attenuation of Aβ25–35 induced elevation of cytosolic Ca^2+ concentration, ROS and glutamate release	[187]
Gingerol	Zmgiber officinale (Zingiberaceae)	In vitro SH-SY5Y human neuroblastoma cells	Attenuation of intracellular ROS and/or reactive nitrogen species and subsequent oxidative and/or nitrosative damages	[181]
Isofraxidin	Eleutherococcus senticosus (Araliaceae)	In vitro Primary cortical neurons	Prevention of Aβ25–35 induced axonal and dendritic atrophy	[138]
Justicidin A	Monsonia angustifolia (Geraniaceae)	In vitro HeLa cells	decreased the formation of Aβ in APPsw-transfected cells	[149]
Luteolin	Elsholtzia rugulosa (Lamiaceae)	In vitro SH-SY5Y human neuroblastoma cells	Suppression of Aβ protein precursor expression, regulation of redox imbalance and attenuation of caspase family related apoptosis	[188]
Methyl 3,4-Dihydroxybenzoate	Kalimeris indica (Asteraceae)	In vitro SH-SY5Y human neuroblastoma cells	Attenuate neuronal cell death, reduce oxidative stress and inhibit apoptosis in cells.	[189]
Nobiletin	Citrus depressa (Rutaceae)	In vivo APP-SL 7–5 transgenic Mice	Increased extracellular signal regulated kinase phosphorylation and attenuation of Aβ-induced inflammation	[190]
Oroxylin A	Scutellaria baicalensis (Lamiaceae)	In vivo ICR mice	Suppression of Aβ25–35 induced astrocyte and microglia activation, iNOS expression and lipid peroxidation	[191]
Paeoniflorin	Paeoniae alba (Paeoniaceae)	PC12 cells	Attenuated neuronal cell death induced by Aβ25–35 via preventing mitochondrial dysfunction, increased cytochrome c as well as caspase 3 and 9 activity	[192]
p-Coumaric acid Ursolic acid	Corni fructus (Cornaceae)	PC12 cells	Attenuated Aβ25–35 induced toxicity via NF-κB signaling pathway	[193]
Penta-o-galloyl-beta- D glucopyranose	Paeonia suffruticosa (Paeoniaceae)	In vitro ThT, and neuroblastoma SK-N-SH cells In vivo Transgenic 2576 mice	Inhibition of oligomer and fibril formation from monomer and destabilization of pre-formed fibrils Inhibition of Aβ production in the rat brain	[150]
Phenolics
Pomiferin	Ficus macrophylla (Moraceae)	In vitro swAPP-N2a cells	Modification of Aβ accumulation by activation of insulin degrading enzyme	[139]
Puerarin	Pueraria lobata (Fabaceae)	PC12 cells	Protect against Abeta25–35 induced neuronal cell death. Also, found to increase the Bcl-2/Bax ratio and reduce caspase-3 activation.	[194]
Rosmarinic acid	Salvia officinalis (Lamiaceae)	In vitro PC12 cells	Inhibition of Aβ-induced ROS formation, lipid peroxidation, DNA fragmentation, caspase-3 activation and tau protein hyperphosphorylation	[195]
4-O-methylhonokiol	Melissa officinalis (Lamiaceae)	In vivo ICR mice, In vitro PC 12 cells,	Inhibition of Aβ1–42 induced ROS generation and neuronal cell death. Also attenuated the formation of Aβ aggregation/fibrillization	[148]
Rutin	Ginkgo biloba (Ginkgoaceae)	In vitro SH-SY5Y human neuroblastoma cells	Inhibit Aβ42 fibrillization and attenuate Aβ42-induced cytotoxicity dose dependently	[196]
Salvianolic acid B	Salvia miltiorrhiza (Lamiaceae)	In vivo ICR mice	Reduced levels of Aβ25–35 induced nitric oxide synthase, cyclooxygenase-2 expression and lipid peroxidation product	[197]
Silibinin	Silybum marianum (Asteraceae)	In vivo ICR mice In vitro SH-SY5Y human neuroblastoma cells	Prevention of oxidative damage in the hippocampus Inhibition of Aβ aggregation and attenuation of Aβ-induced H2O2 Production	[198,199]
Sulfuretin	Albizzia julibrissin (Fabaceae)	In vitro SH-SY5Y human neuroblastoma cells	Protection against Aβ induced neurotoxicity. nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream target of PI3K/Akt	[200]
Tannic acid	Plantago Lanceolata (Plantaginaceae)	In vivo PSAPP mouse model	Significantly reduced both Aβ1–40 and Aβ1–42 production and inhibited β-Secretase activity.	[186]
α-Mangostin	Garcinia mangostana (Clusiaceae)	In vitro primary cortical neurons	Reduction in the Aβ production via inhibiting β-secretase γ-secretase	[201]
Saponins
Akebia saponin B	Dendrocalamus asper (Poaceae)	In vitro PC 12 cells	Inhibition of excessive Ca2+ influx, reduction of LDH leakage and prevention of loss of cell viability	[202]
Cochalinoside A Polanoside A Chikusetsusaponin V	Polaskia chichipe (Cactaceae)	In vitro SH-SY5Y human neuroblastoma cells	Inhibited Aβ aggregation in Aβ40 and Aβ42	[203]
Sugars
Bajijiasu (β- D-fructofuranosyl (2–2) β- D-fructofuranosyl)	Morinda officinalis (Rubiaceae)	PC12 cells	Neuroprotective against Aβ25–35 induced neurotoxicity in PC12 cells, likely by protecting against oxidative stress and ensuing apoptosis likely by expression levels of p21, CDK4, E2F1, Bax, NF-jB p65, and caspase-3	[204]
Fucoidan	Laminaria japonica (Laminariaceae)	In vivo Sprague-Dawley rats	Decrease in oxidative stress and inhibition of acetylcholinesterase	[205]
α-D-(1→4)-glucan	Lonicera japonica (Caprifoliaceae)	In vitro ThT and human neuroblastoma SH-SY5Y cells	Inhibited Aβ42 aggregation, Also, attenuate the cytotoxicity induced by Aβ42 aggregation in cell type.	[206]
Steroids
Acteoside	Verbascum sinuatum (Scrophulariaceae)	In vitro human neuroblastoma SH-SY5Y cells	Modulation of the apoptotic signal pathway via Bcl-2 family, caspase-3 cytochrome c inhibition of ROS production	[207]
Eleutheroside B-E Isofraxidin	Eleutherococcus senticosus (Araliaceae)	In vitro Primary cortical neurons	Prevention of Aβ(25–35) induced axonal and dendritic atrophy	[138]
Ginsenoside Re	Panax ginseng (Araliaceae)	In vitro PC12 cells	Reduction of Aβ-induced cell death	[208]
Rhaponticin	Rhizome rhei (Polygonaceae)	In vitro IMR-32 cells	Reduction of the pro-apoptotic Bax/Bax homodimers through the formation of Bcl-2/Bax heterodimers	[209]
Salidroside	Rhodiola rosea (Crassulaceae)	In vitro SH-SY5Y human neuroblastoma cells	Induction of antioxidant enzymes, downregulation of pro-apoptotic protein Bax and upregulation of anti-apoptotic protein Bcl-extra large	[194]
Withanamide A Withanamide C	Withania somnifera (Solanaceae)	In vitro PC12 cells	Inhibition of free radical generation and fibril formation	[210]
Xylocoside G	Itoa orientalis (Flacourtiaceae)	In vitro SH-SY5Y human neuroblastoma cells	Downregulation of cyclooxygenase-2, attenuation of release of inflammatory factors and repression of caspase-3 activation	[211]
Terpenoids
Alantolactone Isoalantolactone	Inula helenium (Asteraceae)	In vitro cortical neurons In vivo scopolamine induced Nrf2^−/−mice	Attenuated intracellular ROS and superoxide anion in Aβ25–35 induced cortical neurons. Reversed cognitive deficit induced by scopolamine	[212]
Carnosic acid	Rosmarinus officinalis (Lamiaceae)	Aβ induced toxicity rats	Increased the learning and behavior and increased healthy neurons in CA region in brain	[213]
Cryptotanshinone	Salvia miltiorrhiza (Lamiaceae)	In vivo APP/PS1 transgenic mice	Swe/APP cortical neurons increased release of sAPP and reduction in levels of Aβ	[214]
Eugenol	Acorus calamus (Acoraceae)	In vitro PC12 cells	Inhibition of Aβ-induced Ca^2+ intake	[154]

Antioxidants in AD

Oxidative stress is a process of ROS generation, which plays a central role in cellular injuries and various clinical disorders, including neurodegenerative diseases [215]. The brain cells are continuously exposed to a surplus of free radicals, which leads to oxidative stress. Thus, ROS-induced oxidative stress in the brain is one of the most common etiologies of neurodegenerative disorders, including AD [216,217]. The oxidative stress not only mediates neurotoxicity induced by Aβ, but also enhances the production of Aβ [218]. Thus, oxidative stress is a prime contributing factor for AD development, and antioxidants can be considered therapeutic approaches.

MTDL: A new therapeutic approach for AD

For 15 years, AD had been treated symptomatically, and the therapeutic approaches are of modest efficacy [219]. The approved drugs fall into two categories: AChE inhibitors and N-methyl D-aspartate (NMDA) receptor antagonists, with four and one drug in each group, respectively [220,221]. These cholinergic drugs increased cholinergic system deficiency by inhibiting the AChE enzyme, which degrades acetylcholine. One of the important drugs belonging to this class is donepezil. Many evidence infers that AChE inhibition reinstates the cholinergic system and mediates the disease progression [222].

On the other hand, the excessive NMDA glutamate receptor activity observed in AD was inhibited by a low-affinity, non-competitive and open channel blocker, memantine, which is frequently used with AChE inhibitors [219]. These drugs are insufficient for AD therapy, and this warrants more research towards finding drugs against AD. 223,suggested that identification of Aβ or tau proteins as a target in AD created two groups of researchers, referred to as ‘baptists’ and ‘tauists’ [223]. However, both these groups failed to develop the potential drugs which can cure the disease. Moreover, along with Aβ, antagonistic AChE also targets other aspects of AD.

Over the past nine decades, researchers have been targeting one factor at a time, which did not result in any drug to cure AD. Efficient pharmacotherapy may require simultaneous action on several targets involved in its pathogenesis due to the complexity of AD. Such effects may be achieved by administering a drug cocktail or a multicomponent drug. Besides AD, other neurological disorders such as depression, allergies, hypertension, schizophrenia, inflammation, and metabolic diseases can also be treated by this combination of drugs [224]. But, this approach carries the risk of potentially hazardous drug-drug interactions caused by specific pharmacokinetic and pharmacodynamic properties of individual components. It would be ideal if a single molecule could simultaneously act on multiple targets with greater efficacy and safety profile. In 2005, Morphy and Rankovic proposed this innovative strategy to develop MTDLs as potential drug candidates. This approach can be more relevant and practical since AD is a complex neurological disorder with multiple causative factors.

Further, to reduce the side effects, many reports suggest using herbal alternatives to enhance the efficacy of the therapy in the future [225]. Thus, identifying novel pharmacological neuroprotective MTDLs from plants is the new hope for treating AD. These natural products can simultaneously act on multiple targets associated with AD (enhance α-secretase activity; decrease β- and γ- secretase activity; inhibit Aβ; prevent oxidative stress and inflammation). Some plant products possessing multiple targets against AD are presented in tabulated in Table 5. The summary of the role of plant extracts and their phytochemicals in circumventing AD is represented in Figure 3.

Table 5. Plant products with multiple targets against AD

Compounds	Mechanisms	References
Asiatic acid	BACE-1 inhibitor, anti-inflammatory, anti-apoptotic, kinase modulator, α-secretase inhibitor	[226–228]
Berberine	IMAO, anti-neuroinflammatory, cholesterol regulator, insulin regulator	[229,230]
Curcumin	Anti-inflammatory, BACE-1 inhibitor, tau dimerization inhibitor, NMDA receptor modulator (antagonistic), α-secretase inhibitor, metal chelator	[231–236]
Ensaculin	Serotonin 5-HT1A agonist, NMDA receptor modulator (antag.), dopamine D2 receptor antagonist	[237,238]
Epigallocatechin gallate	BACE-1 inhibitor, α-secretase inhibitor, kinase modulator, metal chelator, α-synuclein inhibitor, anti-inflammatory	[239–242]
Ferulic acid	BACE-1 inhibitor, protective against PSEN1 expression	[186,243,244]
Honokiol, Magnolol	Anti-apoptotic, neuroprotective	[245]
Myricetin	Anti-neuroinflammator, NMDA receptor modulator, BACE-1 inhibitor	[246,247]
Nicotine	Adenosine A2 receptor antagonist, IMAO-B	[230]
Osmotin	BACE-1 expression, phosphorylation of p-PI3K, p-Akt and p-GSK3β	[248,249]
Quercetin	Inhibitors of NF-κB induced cytokine production, potential anti-AChE activity	[71,250]
Resveratrol	SIRT1-ROCK1 signaling pathway regulatoBACE-1 in, hibitor, apoptosis modulator, anti-inflammatory	[251; 236, 252–254]
Tannic acid	BACE-1 inhibitor, apoptosis modulator, anti-inflammatory	[255]
Vincamine	SOD and activation of PI3K/Akt pathway, brain circulation modulator, voltage Na+ channel modulator	[170]

Figure 3. The natural products can simultaneously act on multiple targets associated with AD (enhance α-secretase activity; decrease β- and γ- secretase activity; inhibit Aβ; prevent oxidative stress and inflammation).

Conclusion and prospects

Natural products have tremendous potential to act against AD and have given hope to the scientific fraternity as sources of drugs. Though the cause of AD is not clearly understood, natural products with multiple activities like AChE inhibition, NMDAR antagonist, antioxidant ability, amyloid inhibition, and anti-inflammation have the potential to be used as drugs. The healing power of culinary herbs and medicinal plants has attracted the researcher’s attention to study natural products as a potentially valuable resource for drug discovery against AD. Several natural products are used alone or in combination with some other neuroprotective agents to enhance memory and cognitive dysfunction and prevent AD.

Theoretically, phytochemical-based treatments against cognitive deficit could prove beneficial in clinical trials on humans due to their low toxicity and high bioavailability. The use of recent pharmaceutical technologies and developments in medicinal chemistry is to design novel drugs based on natural templates, which act on multiple targets, opens up a new window to using natural products in therapeutics against AD.

Disclosure statement

No potential conflict of interest was reported by the author(s).