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

Figures & data

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.

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]

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]

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.

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]

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).

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