The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease

Abstract

One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer’s disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics’ pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence.

Keywords

Alzheimer’s disease anti-tau molecules disease prevention and treatment mechanisms multitarget approaches nutraceutical compounds

NUTRACEUTICAL COMPOUNDS IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is becoming a major puzzle to medicine and society in general. Aging is the main risk factor for AD, since most cases are related to elderly individuals affected with the so-called “sporadic AD”. Genetically-determined AD by specific mutations occurs only in 1–2% of cases. AD is the most common type of dementia in the senile population [1], a disease that affects all the cognitive capacities of the human being and behavioral aspects as well [2]. The portion of the world population suffering from AD is over 50 million and the disease is in constant expansion (World Alzheimer’s Report). In this context, this epidemic disorder is concerning public health opinion focusing efforts on its prevention and treatment. Moreover, AD is associated with neuropsychiatric distress that occurs before cognitive decline in patients, thus producing an additional problem for the caregivers and family members. In regard with its biological context, two main protein aggregates have been reported: 1) neurofibrillary tangles (NFT), derived from the progressive aggregation of the hyperphosphorylated tau protein, inside neurons that derive from tau assembly into oligomeric structures named “paired helical filaments” [2 –5] and 2) senile plaques, composed by deposits of the amyloid-β (Aβ) peptide of 39 to 42 aminoacidic residues, generated by the proteolytic excision of the amyloid-β precursor protein (AβPP) by the enzymes β - and γ-secretases, in the extracellular space. Both types of pathological polymers promote the loss of synaptic processes and neuronal death [1, 6] (see Fig. 1).

Fig. 1

Neuropathological hallmarks of Alzheimer’s disease and different therapeutic targets for a nutraceutical family of compounds [147 –149].

We proposed that the onset of AD is a consequence of the response of microglial cells upon their activation by “damage signals” that include a large set of molecular or physical factors, which triggers a neuroinflammatory response, production of inflammatory cytokines, and finally tau hyperphosphorylations and misfolding of tau structure [4, 7, 8].

Due to the lack of effective treatments for AD, novel strategies are being implemented to prevent this disease based on dietary changes and nutritional supplements, functional foods, and natural compounds. Innovative treatments, which we are going to review here, are essential to improve the life quality and ameliorate the symptoms of affected subjects. Several pharmacological alternatives have been proposed in recent years to prevent and treat AD, without success when it comes to clinical trials. On this scope, we aim to review and direct our focus on novel natural bioactive compounds, such as those considering the broad picture of this pathology. The neuroimmunomodulatory and anti-inflammatory context is one of the approaches in order to understand AD pathogenesis and potential therapies or preventive actions. We have proposed in previous reports [9, 10] the need to focus onto multitarget therapies provided by multicomponent nutraceutical formulations [11], instead of single-molecule therapies directed to only one target. Here, we are reviewing some of these alternatives, focusing in some cases on their possible molecular mechanisms, their obtention from natural sources, and clinical evaluation.

NATURAL MOLECULES ACTING ON DIFFERENT BRAIN TARGETS IN AD

A list of medicinal plants and natural products is provided in Table 1, indicating the scientific name and some common names of the original source. All of them share the characteristics of showing some level of activity to control AD pathophysiology. Moreover, these medicinal plants have a long tradition of use in Ayurvedic medicine, one of the most ancient medicinal system in the world, and its contribution to AD treatment and prevention is widely supported by Ayurvedic medical records [11, 12]. These medicinal plants include activities such as: a) memory enhancers; b) activity to improve cognitive function; c) anticholinesterase activity; d) mainly activities against the amyloid plaque formation, or e) antioxidant activity. However, in most cases, no major studies were carried out on the active principles or the mechanisms of action. In the following sections of this review, we analyze in depth the natural compounds focused on different targets, and nutraceuticals targeting tau protein. In those cases, more in-depth studies have been carried out toward their mechanisms of action. In some examples, medicinal plants point also to other possible pharmacological actions such anti-stress or anti-inflammatory actions. In this context, we decided to include this information since these medicinal plants could be a potential source for further investigation toward an active principle against AD.

Table 1

List of different compounds from natural and medicinal plants, with anti-Alzheimer’s disease activity. These compounds exert their effects via different brain targets

S. No.	Name of the natural medicinal plants	Plant part	Anti-Alzheimer’s	References
with Scientific and Common name	used	disease activity
1.	Withania somnifera (Ashwagandha)	Root	Anti-amyloid, anticonvulsant, cerebroprotective, anxiolytic, nootropic, rejuvenation	[99 –102]
2	Curcuma longa ( Turmeric)	Rhizome	Antioxidant and anti-amyloidogenic effects	[103]
3.	Bacopa monnieri (Brahmi)	Whole plant	Antioxidant, nootropic, rejuvenation, inhibits acetylcholinesterase	[104, 105]
4.	Convolvulus pluricaulis (Shankhpushpi)	Whole plant	Nootropic, anxiolytic, tranquillizing, antidepressant, anti-stress, anti-amnesic	[106]
5.	Centella asiatica (Mandookaparni)	Whole plant	Modulates antioxidant and mitochondrial pathways and improves cognitive function	[107]
6.	Celastrus paniculatus (Jyotishmati)	Seed	Memory enhancer	[108]
7.	Nardostachys jatamansi (Jatamansi)	Dried rhizome and roots	AChE inhibitor, antioxidant, memory enhancer, anti-inflammatory properties	[109]
8.	Ficus religiosa (Peepal)	Fruit	Acetylcholinesterase inhibitor, anti-amnesic	[110]
9.	Galanthus nivalis (common snowdrop)	Flower	Anti-Alzheimer’s disease	[111]
10.	Ginkgo biloba (Maidenhair tree)	Leaf	Inhibition of Aβ-induced toxicity and cell death.	[112, 113]
11.	Commiphora whighitti (Guggul)	Leaf, stem, fruit, latex and root	Anti-inflammatory efficiency, learning and memory enhancer	[114]
12.	Emblica officinalis (Amla)	Fruit	Memory enhancer	[115]
13.	Glycyrrhiza glabra (Mulethi)	Root	Memory and cognition enhancer	[116]
14.	Lepidium meyenii (Maca)	Memory enhance and ant-amyloid activity	[117, 118]
15.	Magnolia officinalis (houpu magnolia)	Memory impairment, BACE-inhibition activity, anti-Aβ activity, anti-inflammatory	[119, 120]
16.	Panax ginseng (Ginseng)	Root	Acetylcholinesterase inhibitor, improving cognitive abilities	[121]
17.	Zingiber officinale (Adhrak)	Rhizome	Anti-AChE activity, improves amyloid-induced memory impairment in mice	[122]
18.	Crocus sativus (Kesar)	Stigma	Anti-depressant, anti-stress, rejuvenation	[123]
19.	Tinospora cordifolia (Giloy)	Arial plant part	Anti-amyloidogenic, anti-cholinesterase, antioxidant, neuroprotective effects, nootropic ameliorates cognitive deficits associated with glutamate-induced excitotoxicity	[124 –126]
20.	Cissampelos pareira (Velvet-leaf)	Anti-anxiety and anti-depressant effect	[127]
21.	Punica granatum (Anar)	rind of the fruit and bark	Antioxidant activity, acetylcholinesterase inhibitor	[128]
22.	Moringa oleifera (Drumstick Tree)	leaves, roots, seed, bark, fruit, flowers and immature pods	Cholinergic activity, enhance neurogenesis, enhance cognitive effect	[129, 130]
23.	Evolvulus alsinoides (Vishnukranti)	Arial plat part	Adaptogenic, anti-amnesic, improve learning and memory	[131]
24.	Melissa officinalis (Lemon Balm)	Leaf	Nootropic, anxiolytic, antidepressant, anti-stress, anti-amyloid	[132, 133]
25.	Salvia officinalis (Common sage)	Leaf	Anti-nociceptive, anti-inflammatory, anti-amyloidogenic anti-cholinesterase, memory and cognition enhancer	[134, 135]
26.	Ficus racemosa (Goolar Fig)	Leaves, fruits, bark, latex, and sap of the root	Memory enhancing activity, significantly increased acetylcholine level	[136]
27.	Myristica fragrans (Nutmeg)	Seed	Acetylcholinesterase inhibitors, memory-enhancing effect, antioxidant, anti-inflammatory	[137]
28.	Rosa damascene (Gulab)	Flower	Anticonvulsant, anti-amyloidogenic, anti-cholinesterase, antioxidant, neuroprotective effects, nootropic, rejuvenation, memory and cognition enhancer	[138 –140]
29.	Vitis vinifera (Angoor)	Fruit	Anti-amyloidogenic, anti-cholinesterase, antioxidant, memory enhancer	[141, 142]
30.	Lavandula angustifolia (Lavender)	Flower	Anti-Alzheimer’s disease; improves deteriorated synaptic plasticity	[143]
31.	Murraya koenigii (Meethi Neem)	Leaf	Nootropic, rejuvenation, acetylcholinesterase inhibitor	[144]
32.	Prunus amygdalus (Badaam)	Seed	Nootropic, rejuvenation, memory and cognition enhancer	[145, 146]

NATURAL COMPOUNDS AND ANTIOXIDANTS WITH PROVEN ACTIVITY TO CONTROL TAU SELF-ASSEMBLY

Tau protein is hyperphosphorylated in AD, and consequently aggregated into NFTs that lead to the irremediable neuronal cells’ death. Natural products offer many options to reduce the progress and symptoms of AD. Here we review several compounds that have been proven to control tau self-assembly both in vitro and in vivo models. Natural compounds and herbal medicines [11, 12] have been currently evaluated as potential elements for the non-invasive treatment against AD, and whose mechanism of actions appears to be related with tau oligomerization (see Figs. 2 and 3).

Fig. 2

Major natural compounds displaying anti-AD properties.

Fig. 3

Chemical structure of reviewed natural compounds able to inhibit tau self-assembly. 1) Curcumin, 2) Delphinidin, 3) Quercetin, 4) Rosmarinic acid, 5) (–) Epigallocatechin-3-gallate, 6) Resveratrol, 7) Morin, 8) Luteolin, 9) Oleocanthal, 10) Huperzine A, 11) S-allyl-L-cysteine (SAC). (http://www.chemspider.com/).

Polyphenolic molecules and flavonoids

Curcumin is a polyphenol isolated from rhizomes of curcuma longa. With several antioxidative and anti-inflammatory effects, it reduces the expression of COX-2 and iNOS, ameliorating inflammation and damage by reactive oxygen and reactive nitrogen species; it also impairs IL-6, NF-κB, and MAPK signaling pathways, thus reducing astroglial activation; finally it prevents tau aggregation and promotes tau oligomers’ disassemble in vitro. All the latter indicates that curcumin is an excellent candidate to be used in AD patients with cognitive impairment. Since the original molecule has a limited passing through the blood-brain barrier, the derivative biocurcumin is mostly used [12]. Curcumin is a polyphenol derived from turmeric (Curcuma longa) with anti-inflammatory, antioxidant, antitumor, antibacterial, and neuroprotective activities [14 –17]. Numerous studies have shown that curcumin may be a promising compound for the treatment of AD for its action toward Aβ and tau [14 , 18]. Hyperphosphorylated tau and its aggregated forms (NFT) are crucial to the pathogenesis of AD, and several studies have shown that curcumin can prevent tau hyperphosphorylation and neurotoxicity [15]. GSK-3β is an enzyme that regulates the phosphorylation of tau and its inhibition may protect cells from tau-induced neurotoxicity and curcumin has been identified as an inhibitor GSK-3β [15, 19]. Similarly, in human neuroblastoma SHSY5Y cells, curcumin inhibited tau hyperphosphorylation through the phosphatase and tensin homologue (PTEN)/protein kinase B (Akt)/GSK-3β pathway, a cellular signaling pathway induced by Aβ [15, 20]. A dose of 5–10μM of curcumin is associated with PC12 cells protection against Aβ-induced neurotoxicity by inhibiting oxidative damage and tau hyperphosphorylation [14, 21]. On the other hand, in the curcumin-treated nematodes, the amount of acetylated α-tubulin, an indicator of microtubule stabilization, was significantly greater than the non-curcumin treatment group, suggesting that curcumin has the potential to control tau-neurotoxicity by improving microtubule stabilization [15, 22]. This outcome suggests that curcumin may have a role in tau tangle clearance and alleviating p-tau-induced neurotoxicity. Nevertheless, more trials are needed to assess the exact mechanism of curcumin and clinical outcomes in AD, considering its pleiotropic action [14 –16].

Delphinidin is a water-soluble dye belonging to the anthocyanidin group. It is abundant in red wine and berries, characterized by interesting pharmacological activities such as antioxidant and anti-inflammatory properties. Regarding the neuroprotective effect of delphinidin, the current literature suggests that delphinidin inhibits tau hyperphosphorylation and activation of GSK-3β induced by Aβ in PC12 cells [23]. Likewise, it prevents Aβ-induced neurotoxicity through inhibition of intracellular calcium levels [23]. Similar research related to other anthocyanins as cyanidin has demonstrated the planar aromatic ring of anthocyanins is necessary for the inhibition of heparin-induced filament formation of tau protein [24], and have also found that its 3-O glucoside (C3G) can rescue the cognitive impairments that are induced by Aβ via the modulation of GSK-3β/tau [25]. According to the above, it would be interesting to study if the other anthocyanins structurally-related with delphinidin share similar neuroprotective effect, and thus develop a potential anti-AD agent.

Quercetin is a flavanol widely distributed in fruits, herbs, and vegetables, and is especially abundant in onions. It has anti-oxidant, anti-cancer, and anti-inflammatory properties [26, 27]. In in vitro studies, quercetin has been proved to be an effective inhibitor against several aggregation-proteins, such as Aβ, α-synuclein, and tau; via direct interaction with the misfolded proteins causing the stabilization of oligomeric species and inhibition of fibril growth [27].

The pre-treatment of HT22 hippocampal neurons with quercetin can inhibit okadaic acid-induced the hyperphosphorylation of tau protein and oxidative stress [26]. Data suggest that quercetin suppresses tau phosphorylation at Ser396, Ser199, Thr205, and Thr231 and increases phosphorylation of tau-1 (dephosphorylated tau at Ser195/198/199/202) [26, 28]. Quercetin also decreases the activity of GSK3β but increases the activity of Akt (Ser473), evidence that supports that the neuroprotective effects of quercetin are associated with anti-hyperphosphorylation of tau protein via PI3K/Akt/GSK3β signaling pathways [26]. Further experiments have demonstrated that quercetin inhibits the activity of cyclin-dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca^{2 +}calpain-p25-CDK5 signaling pathway [28].

Other findings have demonstrated that in a triple-transgenic mouse model of AD, the administration of quercetin (25 mg/kg) via i.p induced the reduction of NFTs and levels of Aβ, as well as an amelioration in neuroinflammatory process and learning and memory impairment [27, 29]. In summary, quercetin represents a great therapeutic agent to treat AD and other neurodegenerative tauopathies [26, 28], especially due to its ability to cross the blood–brain barrier [27].

Rosmarinic acid is a phenolic carboxylic acid found in culinary herbs such as sage, oregano, basil, thyme, rosemary, and peppermint. This polyphenol has many pharmacological activities, such as antioxidant, antibacterial, anti-inflammatory, anticancer, antiviral, and neuroprotective effects [14]. Rosmarinic acid may decrease the hyperphosphorylation of the tau protein, prevents fibrilization in vitro and reduces β -sheet assembly in tau protein linked to AD [14 , 30–32]. Despite its interesting properties, clinical trials are needed to further demonstrate the efficacy of rosmarinic acid against AD.

Epigallocatechin-3-gallate (EGCG) is a flavonol found mainly in green tea leaves, and it has great interest due to its antioxidant, antitumoral, antibacterial, and neuroprotective activity both in vitro and in vivo [27]. EGCG plays crucial role to prevent tau aggregation: it binds to tau in to its phosphorylation site with an affinity of the same order of magnitude than kinases (0.5 nM) and modify the 3D-structure of tau whose preferential conformation changes in the presence of EGCG, which leading to inhibition of its aggregation [30, 33].

Moreover, the green tea flavonoid EGCG has a robust effect on the degradation of AD-relevant phosphorylated tau species in primary cortical neurons by a different mechanism of phytochemical-induced tau clearance [34]. Interestingly, the EGCG increased the expression of key autophagy adaptor proteins, NDP52 and p62. Both proteins have been shown to interact with tau: NDP52 can bind directly to tau16 and p62 is found associated with NFTs and is implicated in promoting tau clearance, suggesting that EGCG is exerting an effect on tau clearance through modulating the adaptor proteins responsible for targeting substrates to autophagy, without altering basal autophagic flux [34]. According other findings, EGCG interacts in a different way with tau, binding to a partially misfolded intermediate, preventing seeding and rescuing cells from tau-induced toxicity [27, 35]. Anyway, EGCG is a phytochemical that can selectively enhance degradation of phosphorylated tau species in neurons and particularly could have significant implications for ameliorating AD progression.

Resveratrol. Trans-resveratrol is a stilbene and natural polyphenolic phytoalexin produced by several plants in response to injury or attack by pathogens (bacteria or fungi). It is abundant in grapes, red wine, and food products. Several studies have associated resveratrol with anti-cancer, antiviral, anti-aging, anti-inflammatory, antioxidant, cardiovascular, and neuroprotective properties [11].

Resveratrol has been also studied for its potential to protect against hyperphosphorylation and/or mediates dephosphorylation of the tau protein [14, 27]. Interestingly, in a tau transgenic mouse model, tau protein that has been hyperphosphorylated may bind resveratrol and be stabilized in a relatively soluble form, preventing tau from aggregating into tangles [36]. Other findings have demonstrated that when resveratrol is applied to a PS19 mouse model tauopathy, the treatment rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation, and synapse loss in the mouse brain [37]. Resveratrol also induces tau dephosphorylation at PP2A-dependent epitopes through increase in PP2A activity caused by decreased expression of the MID1 ubiquitin ligase that mediates ubiquitin-specific modification and degradation of the catalytic subunit of PP2A when bound to microtubules [38]. In addition, the ability of resveratrol to activate PP2A protein also can inhibits GSK3β induced by AMPK/PI3K/Akt [39], hence, the therapeutic role of resveratrol in AD and other tauopathies.

Morin is a flavonol present in fruits and vegetables, including guava, mock orange, and dyer’s mulberry. It has a role as an antioxidant, an antihypertensive, a hepatoprotective, and anti-inflammatory agent. As neuroprotective agent, morin can inhibit GSK3β activity and block GSK3β-induced tau phosphorylation in vitro [40]. Morin attenuates Aβ-induced tau phosphorylation and protects human neuroblastoma cells against Aβ cytotoxicity [31, 40]. Besides, treatment of 3×Tg-AD mice with morin resulted in reductions in tau hyperphosphorylation and paired helical filament-like immunoreactivity in hippocampal neurons [40]. In addition, morin treatment in APPswe/PS1dE9 double transgenic mice markedly decreased tau hyperphosphorylation via its inhibitory effect on CDK5 signal pathway [41]. Based on the above, morin-based formulations could be considered as promising therapeutic agents against tauopathies, due to its effective inhibitory activity of the kinase-mediated tau hyperphosphorylation in cell culture and in vivo in a mouse model of AD.

Luteolin is a flavone found in fruits, vegetables, and herbs, and exhibits biological properties such as anti-inflammatory, antioxidant, antimicrobial, and neuroprotective effect. In vitro studies demonstrated that luteolin reduces the zinc-induced hyperphosphorylation of the tau protein at Ser262/365, through its antioxidant activity and ability to regulate the tau phosphatase/kinase system [14, 42]. Due to its ability to reduce tau hyperphosphorylation, luteolin has promising potential for AD, yet data from well-designed clinical trials are needed to confirm its protective effect.

Meganatural-az (MN) is a group of polyphenolic extracts derived from grape seeds [43]. It improves cognition and decrease Aβ oligomerization in brains of a mouse model of AD [44]. Also, MN promotes the disassembly of tau oligomers [43, 45]. Thus, this polyphenolic extract has several pathways to promote neuroprotection. Interesting data is expected to come from a clinical trial to be finished in September 2020 (ClinicalTrials.gov Identifier: NCT02033941). This study aims to establish the safety and pharmacokinetics of MN in AD patients. It also will also serve as a step-stone for future studies on MN efficacy against cognitive impairment of AD patients.

Oleocanthal is a polyphenol isolated from extra virgin olive oil. It was shown to have a non-steroidal anti-inflammatory activity similar to ibuprofen. This polyphenol has an inhibitory effect on Aβ fibrillization [46], and also on tau fibrillization as well [47]. In regards to tau oligomerization, oleocanthal prevents tau misfolding and maintains its naturally unfolded state [47]. Oleocanthal forms an adduct with the lysine via initial Schiff base formation and for it, the two aldehyde groups are required to promote its inhibitory activity. Furthermore, oleocanthal does not significantly affect the normal function of tau. Thus, this polyphenol is a potential compound to be considered for the development of novel therapies for neurodegenerative tauopathies.

Other nutraceutical compounds and phytopharmaceutical formulas

Limonoids are phytochemicals of the triterpenoid class which are abundant in sweet or sour-scented citrus fruit and other plants of the families Cucurbitaceae, Rutaceae, and Meliaceae. It has been demonstrated that certain limonoids, nimbin and salannin, isolated from Azadirachta indica, prevents heparin induced cross-β sheet formation and also decreased hydrophobicity, which are characteristic nature of tau aggregation [48]. They also restricted the aggregation of tau to fibrils; in turn, these compounds led to the formation of short and fragile aggregates. In other studies, other limonoids such as gedunin, epoxyazadiradione, azadirone, and azadiradione prevented the formation of tau aggregates and disaggregates previously formed tau aggregates [49], possibly through the interaction with hexapeptide regions of tau oligomers. These compounds were non-toxic to HEK293T cells, thus are an attractive potential compound for the development of novel therapies against AD.

Huperzine A is a sesquiterpene alkaloid group found in Huperzia serrate. This compound enhances learning capacity and memory in transgenic mice in a Morris water maze test due to inhibition of PKC/MAPK, γ-secretases as well as in the increase of phospho-GSK-3 [14]. Also, it has demonstrated antioxidant properties in an AD rat model [31]. A phase II trial of huperzine A in mild to moderate AD showed that huperzine A 200μg did not demonstrate cognitive benefits; however, the huperzine A 400μg can improve the Alzheimer’s Disease Assessment Scale-cognitive and did not induce side effects [14, 31].

Aged garlic extract. Apart from its culinary use, garlic (Allium sativum) is being used to complement the treatment of several ailments like certain forms of cancer and diabetes. Several studies have assessed the neuroprotective effects of aged garlic extract (AGE) and its active ingredients, S-allyl-L-cysteine (SAC). APP-Tg mice treated with AGE or SAC decreases the level of hyperphosphorylated tau in brain due to decreasing the activity of GSK-3β by garlic compounds [50]. AGE or SAC’s anti-amyloid properties can also be helpful for preventing hyperphosphorylation of tau. Interestingly, insulin secretagogue action of garlic compounds can increase the brain levels of insulin and insulin like growth factor (IGF), which can decrease brain Aβ burden and inhibit the activation of GSK-3β and can potentially prevent tau phosphorylation [50]. On the other hand, Tg2576 mice fed with aged garlic extracts exhibited enhanced memory in the hippocampal region [14]. The aged garlic extract and SAC can emerge as a potential therapeutic agent in preventing and treating neurodegenerative disorders such as AD.

Azaphilones are secondary fungal metabolites, usually associated to pigments. Aspergillus nidulans azaphilones derivates inhibited tau filament assembly [51]. Eleven compounds were tested, and out of them, four promoted the dissemblance of tau oligomers in a dose-dependent fashion [51]. When these azaphilones were added to the tau aggregates, they reduced both the total length and numbers of tau polymers [51]. Most importantly, when the most potent compounds were tested to define if they interfere with tau’s normal function of stabilizing microtubules (MTs), they did not completely inhibit MT assembly in the presence of tau [51]. Thus, these fungal metabolites are very promising lead compounds for tau aggregation inhibitors and, more excitingly, for compounds that can disassemble pre-existing tau filaments. They also represent a new class of anti-tau aggregation compounds with a novel structural scaffold.

Brain Up-10^® is a novel formulation containing Andean shilajit (AS) and vitamins B6, B9 and B12. The AS is a fossilized product generated by the action of several types of microbial agents. It derives from a natural peat moss extracted in a desertic area from the Andes of northern Chile. AS is composed mainly by fulvic acids (FA) and humic acids (HA); also, in less extent it has some inorganic molecules such as selenium, magnesium, and other minerals. This formulation is nontoxic to neuronal cell lines at in a wide range of doses, showing also that AS is innocuous in neuronal cell cultures. In a phase I clinical study, this formulation was proven to be safe and without adverse effects. This novel formulation promotes neuritogenesis in hippocampal cells in primary cultures [52, 53]. The latter shows that the AS and the formulation Brain Up-10^®, can increase the outgrowth of neurites in hippocampal and N2a cells in vitro. Complementing the previous results, it was demonstrated that increasing concentrations of FA promotes neuritogenesis in N2a cell line cultures. These results suggest that FA contained in the AS is the responsible of the neurotrophic effects in cells in culture. This neuritogenic effect may be synergistic to the B vitamins complex, which is known to be neuroprotective. In other studies, it was demonstrated that FA not only exerts an action such as an anti-oxidant but also binds specifically to tau and prevents pathological self-assembly in vitro [54]. In addition to all the previous evidence, it has been demonstrated that the formulation of Brain-Up-10^® prevents human tau aggregation in an in vitro system, thus sustaining its neuroprotective role. Furthermore, this formulation when added to aggregated hTAU40 polymers, is able to promote the disassembly of existing tau aggregates [53].

All the natural compounds in-depth reviewed are very promising lead agent for tau aggregation inhibitors and, more strikingly, represent compounds that can disassemble pre-existing tau filaments [11]. The advantageous properties of these molecules include world-wide availability, low cost, and low toxicity with interesting possibility as anti-AD nutraceutical. Despite that their mechanisms of action are variable, all have a role as antioxidant and involve a direct or indirect interaction with tau protein.

THE MECHANISMS INVOLVED IN THE EFFECTS OF NUTRACEUTICALS ON TAU OLIGOMERIZATION IN AD

One of the main neuropathological features in some neurodegenerative disorders is the intracellular deposition of microtubule-associated protein tau as filamentous aggregates. These disorders, commonly known as tauopathies, include Pick’s disease, argyrophilic grain disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and AD, among others [55]. These tau aggregates appear as paired helical filaments, twisted ribbons, or straight filaments, are detergent-insoluble and predominantly composed of oligomeric, hyperphosphorylated tau [56, 57] (see Fig. 4). In AD, NFTs, which are constituted of oligomeric tau, deposit in cells and correlate with neuronal cell loss and cognitive impairment [58]. The anatomical distribution of NFTs is associated with progression of brain dysfunction in this disease, thus suggesting that NFT formation and neuronal cell loss are related [59]. Furthermore, FTDP-17 patients have tau mutations [60], thus, it is plausible that tau dysfunction per se can cause neurodegeneration. The latter was demonstrated as the overexpression of tau in several animal models induced induce neurodegeneration [61 –68]. However, it must be taken into consideration that even though abundance of NFTs correlates positively with cognitive impairment in AD [4, 69], these tau oligomers are not necessarily the ones inducing neurotoxicity. The latter was demonstrated in a study where attenuation of tau overexpression in a transgenic mouse model prevented neuronal loss and cognitive impairment even though NFTs remained the same [70].

Fig. 4

Graphical model illustrates the mechanism of action of natural compounds in the control of tau self-assembly, of relevance in AD. The natural compounds can inhibit tau protein NFTs formation in Alzheimer’s disease via protein kinase suppression (GSK-3β or CDK5) or phosphatase activation (PP2A), enzymes responsible for tau protein hyper/des phosphorylation. The natural compounds can also reduce Aβ-load preventing excessive phosphorylation of tau. GSK-3β, Glycogen synthase kinase 3 beta; CDK5, Cyclin-dependent kinase 5; PP2A, Protein phosphatase 2; P-tau; phosphorylated tau.

To further study the mechanism of tau oligomerization, recombinant tau protein was assessed. This rTau protein do not oligomerize spontaneously when incubated at physiological pH, temperature, ionic strength, and concentration (1–10μM) [71], contrary to Aβ peptide [72] and α-synuclein [73]. In vitro tau polymerization required inducer molecules such as RNA, heparan sulfate, arachidonic acid, or heparin [74 –77].

When analyzed, full-length tau polymerization at physiological concentrations was more rapid with arachidonic acid than with heparin [78]. The latter could be due to the fact that it acts in micellar form and promotes fibrillization by binding tau on their anionic surfaces and proceeds via a partially folded thioflavine S (ThS)-positive intermediate [79, 80], which is time dependent but do not display a lag phase [80, 81]. Taking into consideration ThS and stability, it is plausible that the intermediate is constituted by a partially folded tau molecule with a enriched β -sheet structure [71].

In heparin-induced tau polymerization there is a pronounced lag phase [78, 82], which only can be reduced by addition of nucleation seeds. Due to its polyanionic nature (several sulfate groups), it is possible that the negative charges provide a substrate similar to the surface of the microtubule [83, 84]. Since none of the heparin molecules assembled with tau during its polymerization, it is suggested that heparin plays a kinetic rather than a structural role [84].

Are these molecules physiologically relevant? Normally, the levels of free cytoplasmic arachidonic acid are quite low, but the level of cytoplasmic free fatty acids can become highly elevated under certain circumstances such as ischemia [85]. Specifically, in AD there is an increase in the activity of cytoplasmic phospholipase2, thus increasing the levels of fatty acids and their metabolites [85]. Glycosaminoglycans (e.g., heparan sulfate) showed an association with the NFT pathology in AD [86, 87].

Regarding how tau oligomers are associated with cognitive impairment, it has been shown that granular tau oligomers were increased in the frontal cortices at Braak stage I [88], thus, tau dysfunction in the frontal cortex was observed first, prior to the formation of NFTs in entorhinal cortex and cognitive dysfunction symptomatology. These granular tau oligomers in frontal cortex remained constant in Braak stages I–V samples [88]. However, possibly due to the influence of the Aβ peptide, the density of NFTs increases progressively in these stages, as it could accelerate the formation of granular tau oligomers ultimately leading to NFT formation and memory loss.

But memory loss and cognitive impairment possibly occur before NFT formation, as inhibition of mutant tau overexpression in rTg4510 mice prevented neuronal death and improved cognition [70], but NFTs were still present.

Then, it was plausible that other tau multimers played a more prominent role in cognitive impairment. Tau multimers (tau140 and tau170) showed a negative correlation with memory index when evaluated in a Morris water maze [89]. The latter is consistent with the accumulation of tau species (and memory loss) in rTg4510 mice [90].

The oligomeric insoluble form of tau may not be required for the development of cognitive impairment, as a correlation between tau 140 multimers and memory index was observed in young rTg4510 mice, when insoluble tau was not detectable [90]. The latter is consistent with the fact that the onset of motor impairment correlated with the increased levels of tau multimers in the JNPL3 mice [90]. All the above allowed the authors to conclude that the accumulation of larger tau species, but not NFTs, was more proficiently correlated with cognitive impairment [90].

It was demonstrated that tau larger species and oligomers are constituted by hyperphosphorylated tau [88]. This post translational modification decreases the rate of tau turnover, leading to conformational state change that eventually leads to a reduced capacity to bind microtubules, actin filaments, and plasma membranes [91 –94]. Specifically, in AD, a minimum of 30 serine/threonine residues of tau are phosphorylated [95, 96], and the level of phosphorylation is possibly correlated with severity of the pathology [97]. Purified phospho-tau is capable of self-polymerization in vitro without inducer molecules [98]. Also, hyperphosphorylated tau is able to sequester tau protein from microtubules [56], thus it is plausible that hyperphosphorylated tau could trigger tau polymerization, and form toxic aggregates that may impair neuronal function. However, the relation between tau aggregation, tau phosphorylation, and neuronal dysfunction remains to be clarified.

Footnotes

ACKNOWLEDGMENTS

This research has been supported by a CORFO grants and by the Ricardo Benjamin Maccioni Foundation and the Indian Scientific Education and Technology Foundation. We thank Leonardo Guzman-Martinez and Constanza Maccioni for help in the preparation of this paper.

Authors’ disclosures available online ().

References

Bettens

, Sleegers

, Van Broeckhoven

(2010) Current status on Alzheimer disease molecular genetics: From past, to present, to future. Hum Mol Genet 19, R4–R11.

Maccioni

, Munoz

, Barbeito

(2001) The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch Med Res 32, 367–381.

Maccioni

(2012) Introductory remarks. Molecular, biological and clinical aspects of Alzheimer’s disease. Arch Med Res 43, 593–594.

Farias

, Cornejo

, Jimenez

, Guzman

, Maccioni

(2011) Mechanisms of tau self-aggregation and neurotoxicity. Curr Alzheimer Res 8, 608–614.

Guzman-Martinez

, Farias

, Maccioni

(2013) Tau oligomers as potential targets for Alzheimer’s diagnosis and novel drugs. Front Neurol 4, 167.

Lambert

, Schraen-Maschke

, Richard

, Fievet

, Rouaud

, Berr

, Dartigues

, Tzourio

, Alperovitch

, Buee

, Amouyel

(2009) Association of plasma amyloid beta with risk of dementia: The prospective Three-City Study. Neurology 73, 847–853.

Maccioni

, Rojo

, Fernandez

, Kuljis

(2009) The role of neuroimmunomodulation in Alzheimer’s disease. Ann N Y Acad Sci 1153, 240–246.

Fernandez

, Rojo

, Kuljis

, Maccioni

(2008) The damage signals hypothesis of Alzheimer’s disease pathogenesis. J Alzheimers Dis 14, 329–333.

Guzman-Martinez

, Maccioni

, Andrade

, Navarrete

, Pastor

, Ramos-Escobar

(2019) Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol 10, 1008.

10.

Maccioni

, Tapia

, Guzman-Martinez

(2018) Pathway to tau modifications and the origins of Alzheimer’s disease. Arch Med Res 49, 130–131.

11.

Anekonda

, Reddy

(2006) Neuronal protection by sirtuins in Alzheimer’s disease. J Neurochem 96, 305–313.

12.

Bhatti

, Reddy

, Bhatti

(2019) Lifestyle modifications and nutritional interventions in aging-associated cognitive decline and Alzheimer’s disease. Front Aging Neurosci 11, 369.

13.

Morales

, Cerda-Troncoso

, Andrade

, Maccioni

(2017) The natural product curcumin as a potential coadjuvant in Alzheimer’s treatment. J Alzheimers Dis 60, 451–460.

14.

Bui

, Nguyen

(2017) Natural product for the treatment of Alzheimer’s disease. J Basic Clin Physiol Pharmacol 28, 413–423.

15.

Tang

, Taghibiglou

(2017) The mechanisms of action of curcumin in Alzheimer’s disease. J Alzheimers Dis 58, 1003–1016.

16.

Ana C. Carvalho

ACG

, Cristina

Pereira-Wilson

, Cristovao

F.Lima

(2016) Mechanisms of action of curcumin on aging: Nutritional and pharmacological applications. In Molecular Basis of Nutrition And Aging, Malavolta

, Mocchegiani

, eds. Academic Press, pp. 491–511.

17.

Reddy

, Manczak

, Yin

, Grady

, Mitchell

, Tonk

, Kuruva

, Bhatti

, Kandimalla

, Vijayan

, Kumar

, Wang

, Pradeepkiran

, Ogunmokun

, Thamarai

, Quesada

, Boles

, Reddy

(2018) Protective effects of indian spice curcumin against amyloid-beta in Alzheimer’s disease. J Alzheimers Dis 61, 843–866.

18.

Reddy

, Manczak

, Yin

, Grady

, Mitchell

, Kandimalla

, Kuruva

(2016) Protective effects of a natural product, curcumin, against amyloid beta induced mitochondrial and synaptic toxicities in Alzheimer’s disease. J Investig Med 64, 1220–1234.

19.

Di Martino

, De Simone

, Andrisano

, Bisignano

, Bisi

, Gobbi

, Rampa

, Fato

, Bergamini

, Perez

, Martinez

, Bottegoni

, Cavalli

, Belluti

(2016) Versatility of the curcumin scaffold: Discovery of potent and balanced dual BACE-1 and GSK-3beta inhibitors. J Med Chem 59, 531–544.

20.

Huang

, Tang

, Xu

, Jiang

(2014) Curcumin attenuates amyloid-beta-induced tau hyperphosphorylation in human neuroblastoma SH-SY5Y cells involving PTEN/Akt/GSK-3beta signaling pathway. J Recept Signal Transduct Res 34, 26–37.

21.

Veldman

, Jia

, Halldin

, Svedberg

(2016) Amyloid binding properties of curcumin analogues in Alzheimer’s disease postmortem brain tissue. Neurosci Lett 630, 183–188.

22.

Miyasaka

, Xie

, Yoshimura

, Shinzaki

, Yoshina

, Kage-Nakadai

, Mitani

, Ihara

(2016) Curcumin improves tau-induced neuronal dysfunction of nematodes. Neurobiol Aging 39, 69–81.

23.

Kim

, Sul

, Lim

, Lee

, Joo

, Hwang

, Park

(2009) Delphinidin ameliorates beta-amyloid-induced neurotoxicity by inhibiting calcium influx and tau hyperphosphorylation. Biosci Biotechnol Biochem 73, 1685–1689.

24.

Hattori

, Sugino

, Minoura

, In

, Sumida

, Taniguchi

, Tomoo

, Ishida

(2008) Different inhibitory response of cyanidin and methylene blue for filament formation of tau microtubule-binding domain. Biochem Biophys Res Commun 374, 158–163.

25.

Qin

, Zhang

, Qin

(2013) Protective effect of cyanidin 3-O-glucoside on beta-amyloid peptide-induced cognitive impairment in rats. Neurosci Lett 534, 285–288.

26.

Jiang

, Luo

, Li

, Zhou

, Shen

, He

, Xu

, Wang

(2016) Quercetin protects against okadaic acid-induced injury via MAPK and PI3K/Akt/GSK3beta signaling pathways in HT22 hippocampal neurons. PLoS One 11, e0152371.

27.

Dhouafli

, Cuanalo-Contreras

, Hayouni

, Mays

, Soto

, Moreno-Gonzalez

(2018) Inhibition of protein misfolding and aggregation by natural phenolic compounds. Cell Mol Life Sci 75, 3521–3538.

28.

Shen

, Luo

, Li

, Ting

, He

, Xu

, Wang

(2018) Quercetin inhibits okadaic acid-induced tau protein hyperphosphorylation through the Ca2+calpainp25CDK5 pathway in HT22 cells. Int J Mol Med 41, 1138–1146.

29.

Sabogal-Guaqueta

, Munoz-Manco

, Ramirez-Pineda

, Lamprea-Rodriguez

, Osorio

, Cardona-Gomez

(2015) The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 93, 134–145.

30.

Freyssin

, Page

, Fauconneau

, Rioux Bilan

(2018) Natural polyphenols effects on protein aggregates in Alzheimer’s and Parkinson’s prion-like diseases. Neural Regen Res 13, 955–961.

31.

Andrade

, Ramalho

, Loureiro

, Pereira

MDC

(2019) Natural compounds for Alzheimer’s disease therapy: A systematic review of preclinical and clinical studies. Int J Mol Sci 20, 2313.

32.

Cornejo

, Aguilar Sandoval

, Caballero

, Machuca

, Munoz

, Caballero

, Perry

, Ardiles

, Areche

, Melo

(2017) Rosmarinic acid prevents fibrillization and diminishes vibrational modes associated to beta sheet in tau protein linked to Alzheimer’s disease. J Enzyme Inhib Med Chem 32, 945–953.

33.

Gueroux

, Fleau

, Slozeck

, Laguerre

, Pianet

(2017) Epigallocatechin 3-gallate as an inhibitor of tau phosphorylation and aggregation: A molecular and structural insight. J Prev Alzheimers Dis 4, 218–225.

34.

Chesser

, Ganeshan

, Yang

, Johnson

(2016) Epigallocatechin-3-gallate enhances clearance of phosphorylated tau in primary neurons. Nutr Neurosci 19, 21–31.

35.

Wobst

, Sharma

, Diamond

, Wanker

, Bieschke

(2015) The green tea polyphenol (–)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett 589, 77–83.

36.

, Kwan

, Cheung

SKK

, Ho

, Baum

(2018) Effects of resveratrol and morin on insoluble tau in tau transgenic mice. Transl Neurosci 9, 54–60.

37.

Sun

, Dong

, Zhu

, Sun

, Zhang

, Qiu

, Yu

, Liu

(2019) Resveratrol rescues tau-induced cognitive deficits and neuropathology in a mouse model of tauopathy. Curr Alzheimer Res 16, 710–722.

38.

Schweiger

, Matthes

, Posey

, Kickstein

, Weber

, Hettich

, Pfurtscheller

, Ehninger

, Schneider

, Krauss

(2017) Resveratrol induces dephosphorylation of tau by interfering with the MID1-PP2A complex. Sci Rep 7, 13753.

39.

Shati

, Alfaifi

(2019) Trans-resveratrol inhibits tau phosphorylation in the brains of control and cadmium chloride-treated rats by activating PP2A and PI3K/Akt induced-inhibition of GSK3beta. Neurochem Res 44, 357–373.

40.

Gong

, Park

, Kim

, Piao

, Lee

, Jo

, Chung

, Ha

, Mattson

, Lee

(2011) Morin attenuates tau hyperphosphorylation by inhibiting GSK3beta. Neurobiol Dis 44, 223–230.

41.

, Qu

, Zhang

, Bai

, Zhou

, Zhang

, Li

, Miao

(2016) Morin reverses neuropathological and cognitive impairments in APPswe/PS1dE9 mice by targeting multiple pathogenic mechanisms. Neuropharmacology 108, 1–13.

42.

Zhou

, Chen

, Xiong

, Li

, Qu

(2012) Luteolin reduces zinc-induced tau phosphorylation at Ser262/356 in an ROS-dependent manner in SH-SY5Y cells. Biol Trace Elem Res 149, 273–279.

43.

Pasinetti

, Ho

(2010) Role of grape seed polyphenols in Alzheimer’s disease neuropathology. Nutr Diet Suppl 2010, 97–103.

44.

Wang

, Ho

, Zhao

, Ono

, Rosensweig

, Chen

, Humala

, Teplow

, Pasinetti

(2008) Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci 28, 6388–6392.

45.

, Yemul

, Wang

, Pasinetti

(2009) Grape seed polyphenolic extract as a potential novel therapeutic agent in tauopathies. J Alzheimers Dis 16, 433–439.

46.

Abuznait

, Qosa

, Busnena

, El Sayed

, Kaddoumi

(2013) Olive-oil-derived oleocanthal enhances beta-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: in vitro and in vivo studies. ACS Chem Neurosci 4, 973–982.

47.

, Sperry

, Crowe

, Trojanowski

, Smith

3rd , Lee

(2009) Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem 110, 1339–1351.

48.

Gorantla

, Das

, Mulani

, Thulasiram

, Chinnathambi

(2019) Neem derivatives inhibits tau aggregation. J Alzheimers Dis Rep 3, 169–178.

49.

Gorantla

, Das

, Chidambaram

, Dubey

, Mulani

, Thulasiram

, Chinnathambi

(2020) Basic limonoid modulates chaperone-mediated proteostasis and dissolve tau fibrils. Sci Rep 10, 4023.

50.

Ray

, Chauhan

, Lahiri

(2011) The “aged garlic extract:” (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer’s disease (AD). Curr Med Chem 18, 3306–3313.

51.

Paranjape

, Riley

, Somoza

, Oakley

, Wang

, Prisinzano

, Oakley

, Gamblin

(2015) Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. ACS Chem Neurosci 6, 751–760.

52.

Carrasco-Gallardo

, Farias

, Fuentes

, Crespo

, Maccioni

(2012) Can nutraceuticals prevent Alzheimer’s disease? Potential therapeutic role of a formulation containing shilajit and complex B vitamins. Arch Med Res 43, 699–704.

53.

Andrade

, Guzmán-Martínez

, Cortés

, Maccioni

(2020) The promise for Alzheimer’s disease treatment: Bioactive compounds. In Natural Medicines: Clinical Efficacy, Safety, and Quality, Ghosh

, Mukherjee

, eds. CRC Press.

54.

Cornejo

, Jimenez

, Caballero

, Melo

, Maccioni

(2011) Fulvic acid inhibits aggregation and promotes disassembly of tau fibrils associated with Alzheimer’s disease. J Alzheimers Dis 27, 143–153.

55.

Lee

, Goedert

, Trojanowski

(2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24, 1121–1159.

56.

Alonso

, Zaidi

, Novak

, Grundke-Iqbal

, Iqbal

(2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 98, 6923–6928.

57.

Chen

, Mobley

(2019) Alzheimer disease pathogenesis: Insights from molecular and cellular biology studies of oligomeric Abeta and tau species. Front Neurosci 13, 659.

58.

Gomez-Isla

, Hollister

, West

, Mui

, Growdon

, Petersen

, Parisi

, Hyman

(1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41, 17–24.

59.

Ihara

(2001) PHF and PHF-like fibrils–cause or consequence? Neurobiol Aging 22, 123–126.

60.

Reed

, Wszolek

, Hutton

(2001) Phenotypic correlations in FTDP-17. Neurobiol Aging 22, 89–107.

61.

Allen

, Ingram

, Takao

, Smith

, Jakes

, Virdee

, Yoshida

, Holzer

, Craxton

, Emson

, Atzori

, Migheli

, Crowther

, Ghetti

, Spillantini

, Goedert

(2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22, 9340–9351.

62.

Gotz

, Chen

, Barmettler

, Nitsch

(2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276, 529–534.

63.

Lewis

, McGowan

, Rockwood

, Melrose

, Nacharaju

, Van Slegtenhorst

, Gwinn-Hardy

, Paul Murphy

, Baker

, Yu

, Duff

, Hardy

, Corral

, Lin

, Yen

, Dickson

, Davies

, Hutton

(2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25, 402–405.

64.

Tatebayashi

, Miyasaka

, Chui

, Akagi

, Mishima

, Iwasaki

, Fujiwara

, Tanemura

, Murayama

, Ishiguro

, Planel

, Sato

, Hashikawa

, Takashima

(2002) Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci U S A 99, 13896–13901.

65.

Tanemura

, Akagi

, Murayama

, Kikuchi

, Murayama

, Hashikawa

, Yoshiike

, Park

, Matsuda

, Nakao

, Sun

, Sato

, Yamaguchi

, Takashima

(2001) Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis 8, 1036–1045.

66.

Schindowski

, Bretteville

, Leroy

, Begard

, Brion

, Hamdane

, Buee

(2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169, 599–616.

67.

Eckermann

, Mocanu

, Khlistunova

, Biernat

, Nissen

, Hofmann

, Schonig

, Bujard

, Haemisch

, Mandelkow

, Zhou

, Rune

, Mandelkow

(2007) The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282, 31755–31765.

68.

Yoshiyama

, Higuchi

, Zhang

, Huang

, Iwata

, Saido

, Maeda

, Suhara

, Trojanowski

, Lee

(2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351.

69.

Grober

, Dickson

, Sliwinski

, Buschke

, Katz

, Crystal

, Lipton

(1999) Memory and mental status correlates of modified Braak staging. Neurobiol Aging 20, 573–579.

70.

Santacruz

, Lewis

, Spires

, Paulson

, Kotilinek

, Ingelsson

, Guimaraes

, DeTure

, Ramsden

, McGowan

, Forster

, Yue

, Orne

, Janus

, Mariash

, Kuskowski

, Hyman

, Hutton

, Ashe

(2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481.

71.

Kuret

, Chirita

, Congdon

, Kannanayakal

, Li

, Necula

, Yin

, Zhong

(2005) Pathways of tau fibrillization. Biochim Biophys Acta 1739, 167–178.

72.

Lomakin

, Chung

, Benedek

, Kirschner

, Teplow

(1996) On the nucleation and growth of amyloid beta-protein fibrils: Detection of nuclei and quantitation of rate constants. Proc Natl Acad Sci U S A 93, 1125–1129.

73.

Crowther

, Jakes

, Spillantini

, Goedert

(1998) Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett 436, 309–312.

74.

Perez

, Valpuesta

, Medina

, Montejo de Garcini

, Avila

(1996) Polymerization of tau into filaments in the presence of heparin: The minimal sequence required for tau-tau interaction. J Neurochem 67, 1183–1190.

75.

Kampers

, Friedhoff

, Biernat

, Mandelkow

(1996) RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett 399, 344–349.

76.

Goedert

, Jakes

, Spillantini

, Hasegawa

, Smith

, Crowther

(1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553.

77.

Wilson

, Binder

(1997) Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am J Pathol 150, 2181–2195.

78.

Barghorn

, Mandelkow

(2002) Toward a unified scheme for the aggregation of tau into Alzheimer paired helical filaments. Biochemistry 41, 14885–14896.

79.

Chirita

, Necula

, Kuret

(2003) Anionic micelles and vesicles induce tau fibrillization in vitro. J Biol Chem 278, 25644–25650.

80.

Chirita

, Kuret

(2004) Evidence for an intermediate in tau filament formation. Biochemistry 43, 1704–1714.

81.

King

, Ahuja

, Binder

, Kuret

(1999) Ligand-dependent tau filament formation: Implications for Alzheimer’s disease progression. Biochemistry 38, 14851–14859.

82.

Friedhoff

, Schneider

, Mandelkow

(1998) Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution. Biochemistry 37, 10223–10230.

83.

Makrides

, Shen

, Bhatia

, Smith

, Thimm

, Lal

, Feinstein

(2003) Microtubule-dependent oligomerization of tau. Implications for physiological tau function and tauopathies. J Biol Chem 278, 33298–33304.

84.

von Bergen

, Barghorn

, Muller

, Pickhardt

, Biernat

, Mandelkow

, Davies

, Aebi

, Mandelkow

(2006) The core of tau-paired helical filaments studied by scanning transmission electron microscopy and limited proteolysis. Biochemistry 45, 6446–6457.

85.

Farooqui

, Horrocks

(2006) Phospholipase A2-generated lipid mediators in the brain: The good, the bad, and the ugly. Neuroscientist 12, 245–260.

86.

, Cummings

, Cotman

(1992) Localization of heparan sulfate glycosaminoglycan and proteoglycan core protein in aged brain and Alzheimer’s disease. Neuroscience 51, 801–813.

87.

Diaz-Nido

, Wandosell

, Avila

(2002) Glycosaminoglycans and beta-amyloid, prion and tau peptides in neurodegenerative diseases. Peptides 23, 1323–1332.

88.

Maeda

, Sahara

, Saito

, Murayama

, Ikai

, Takashima

(2006) Increased levels of granular tau oligomers: An early sign of brain aging and Alzheimer’s disease. Neurosci Res 54, 197–201.

89.

Janus

(2004) Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learn Mem 11, 337–346.

90.

Berger

, Roder

, Hanna

, Carlson

, Rangachari

, Yue

, Wszolek

, Ashe

, Knight

, Dickson

, Andorfer

, Rosenberry

, Lewis

, Hutton

, Janus

(2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27, 3650–3662.

91.

Selden

, Pollard

(1983) Phosphorylation of microtubule-associated proteins regulates their interaction with actin filaments. J Biol Chem 258, 7064–7071.

92.

Billingsley

, Kincaid

(1997) Regulated phosphorylation and dephosphorylation of tau protein: Effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J 323 (Pt 3), 577–591.

93.

Arrasate

, Perez

, Avila

(2000) Tau dephosphorylation at tau-1 site correlates with its association to cell membrane. Neurochem Res 25, 43–50.

94.

Vincent

, Rosado

, Kim

, Davies

(1994) Increased production of paired helical filament epitopes in a cell culture system reduces the turnover of tau. J Neurochem 62, 715–723.

95.

Gong

, Liu

, Grundke-Iqbal

, Iqbal

(2005) Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm (Vienna) 112, 813–838.

96.

Morishima-Kawashima

, Hasegawa

, Takio

, Suzuki

, Yoshida

, Titani

, Ihara

(1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J Biol Chem 270, 823–829.

97.

Augustinack

, Schneider

, Mandelkow

, Hyman

(2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103, 26–35.

98.

Wilson

, Binder

(1995) Polymerization of microtubule-associated protein tau under near-physiological conditions. J Biol Chem 270, 24306–24314.

99.

Durg

, Dhadde

, Vandal

, Shivakumar

, Charan

(2015) Withania somnifera (Ashwagandha) in neurobehavioural disorders induced by brain oxidative stress in rodents: A systematic review and meta-analysis. J Pharm Pharmacol 67, 879–899.

100.

Mancini

, Minniti

, Gregori

, Sancini

, Cagnotto

, Couraud

, Ordonez-Gutierrez

, Wandosell

, Salmona

, Re

(2016) The hunt for brain Abeta oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease. Nanomedicine 12, 43–52.

101.

Mishra

, Singh

, Dagenais

(2000) Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): A review. Altern Med Rev 5, 334–346.

102.

Orru

, Casu

, Tambaro

, Marchese

, Casu

, Ruiu

(2016) Withania somnifera (L.) Dunal root extract alleviates formalin-induced nociception in mice: Involvement of the opioidergic system. Behav Pharmacol 27, 57–68.

103.

Shytle

, Bickford

, Rezai-zadeh

, Hou

, Zeng

, Tan

, Sanberg

, Roschek

Jr. , Fink

, Alberte

(2009) Optimized turmeric extracts have potent anti-amyloidogenic effects. Curr Alzheimer Res 6, 564–571.

104.

Aguiar

, Borowski

(2013) Neuropharmacological review of the nootropic herb Bacopa monnieri. Rejuvenation Res 16, 313–326.

105.

Abdul Manap

, Vijayabalan

, Madhavan

, Chia

, Arya

, Wong

, Rizwan

, Bindal

, Koshy

(2019) Bacopa monnieri, a neuroprotective lead in Alzheimer disease: A review on its properties, mechanisms of action, and preclinical and clinical studies. Drug Target Insights 13, 1177392819866412.

106.

Agarwa

, Sharma

, Fatima

, Jain

(2014) An update on Ayurvedic herb Convolvulus pluricaulis Choisy. Asian Pac J Trop Biomed 4, 245–252.

107.

Gray

, Harris

, Quinn

, Soumyanath

(2016) Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice. J Ethnopharmacol 180, 78–86.

108.

Bhanumathy

, Harish

, Shivaprasad

, Sushma

(2010) Nootropic activity of Celastrus paniculatus seed. Pharm Biol 48, 324–327.

109.

Rahman

, Muralidharan

, Anand

(2011) Inhibition of AChE and antioxidant activities are probable mechanism of Nardostacys jatamansi DC in sleep deprived Alzheimer’s mice model. Int J Pharm Tech Res 3, 1807–1816.

110.

Kaur

, Singh

, Goel

(2010) Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia. Pharm Biol 48, 234–240.

111.

Heinrich

, Lee Teoh

(2004) Galanthamine from snowdrop–the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol 92, 147–162.

112.

Bastianetto

, Ramassamy

, Dore

, Christen

, Poirier

, Quirion

(2000) The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci 12, 1882–1890.

113.

Singh

, Barreto

, Aliev

, Echeverria

(2017) Ginkgo biloba as an alternative medicine in the treatment of anxiety in dementia and other psychiatric disorders. Curr Drug Metab 18, 112–119.

114.

Bhatia

, Bharti

, Tripathi

, Mishra

, Sidhu

, Roy

, Nautiyal

(2015) Metabolic profiling of Commiphora wightii (guggul) reveals a potential source for pharmaceuticals and nutraceuticals. Phytochemistry 110, 29–36.

115.

Vasudevan

, Parle

(2006) Pharmacological actions of Thespesia populnea relevant to Alzheimer’s disease. Phytomedicine 13, 677–687.

116.

Cui

, Ao

, Li

, Yu

(2008) Effect of glabridin from Glycyrrhiza glabra on learning and memory in mice. Planta Med 74, 377–380.

117.

Rubio

, Dang

, Gong

, Liu

, Chen

, Gonzales

(2007) Aqueous and hydroalcoholic extracts of Black Maca (Lepidium meyenii) improve scopolamine-induced memory impairment in mice. Food Chem Toxicol 45, 1882–1890.

118.

Alquraini

, Waggas

, Böhlke

, Maher

, Pino-Figueroa

(2014) Neuroprotective effects of Lepidium meyenii (Maca) and macamides against amyloid-beta (25-35) induced toxicity in B-35 neuroblastoma cells.657. FASEB J 28, 613.

119.

Lee

, Choi

, Han

, Kim

, Hwang

, Kang

, Lee

, Oh

, Hong

(2012) Inhibitory effect of ethanol extract of Magnolia officinalis on memory impairment and amyloidogenesis in a transgenic mouse model of Alzheimer’s disease via regulating beta-secretase activity. Phytother Res 26, 1884–1892.

120.

Xie

, Zhao

, Wang

, Jiang

, Yang

, Fu

, Zeng

, Holscher

, Xu

, Zhang

(2020) Magnolol alleviates Alzheimer’s disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-gamma. Biomed Pharmacother 124, 109886.

121.

Jang

, Ahn

, Jo

, Kim

, Sung

, Lee

, Park

, Jin DHm Joo

(2019) Double-processed ginseng berry extracts enhance learning and memory in an Aβ42-induced Alzheimer’s mouse model. Korean J Food Sci Techn 51, 160–168.

122.

Kim

, Shrestha

, Kim

, Ham

, Kim

, Noh

, Kim

, Jo

, Kim

, Moon

, Lee

, Jeong

, Leem

(2019) WS-5 extract of Curcuma longa, Chaenomeles sinensis, and Zingiber officinale contains anti-AChE compounds and improves beta-amyloid-induced memory impairment in mice. Evid Based Complement Alternat Med 2019, 5160293.

123.

Noorbala

, Akhondzadeh

, Tahmacebi-Pour

, Jamshidi

(2005) Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: A double-blind, randomized pilot trial. J Ethnopharmacol 97, 281–284.

124.

Kosaraju

, Chinni

, Roy

, Kannan

, Antony

, Kumar

(2014) Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism. Indian J Pharmacol 46, 176–180.

125.

Sankhala

, Saini

(2012) A review on chemical and biological properties of Tinospora cordifolia. Int J Med Arom Plants 2, 340–344.

126.

Sharma

, Kalotra

, Bajaj

, Singh

, Kaur

(2020) Butanol extract of Tinospora cordifolia ameliorates cognitive deficits associated with glutamate-induced excitotoxicity: A mechanistic study using hippocampal neurons. Neuromolecular Med 22, 81–99.

127.

Beheshti

, Hosseini

, Hashemzehi

, Soukhtanloo

, Khazaei

, Shafei

(2019) The effects of PPAR-gamma agonist pioglitazone on hippocampal cytokines, brain-derived neurotrophic factor, memory impairment, and oxidative stress status in lipopolysaccharide-treated rats. Iran J Basic Med Sci 22, 940–948.

128.

Morzelle

, Salgado

, Massarioli

, Bachiega

, de Oliveira Rios

, Alencar

, Schwember

, de Camargo

(2019) Potential benefits of phenolics from pomegranate pulp and peel in Alzheimer’s disease: Antioxidant activity and inhibition of acetylcholinesterase. J Food Bioact 5, 136–141.

129.

Ganguly

, Hazra

, Ray

, Guha

(2010) Effect of Moringa oleifera in experimental model of Alzheimer’s disease: Role of antioxidants. Ann Neurosci 12, 33–36.

130.

Zhou

, Yang

, Suo

, Li

, Peng

, Xu

, Zeng

, Ren

, Wang

, Zhou

, Zhao

, Yang

, Jin

(2018) Moringa oleifera seed extract alleviates scopolamine-induced learning and memory impairment in mice. Front Pharmacol 9, 389.

131.

Nahata

, Patil

, Dixit

(2010) Effect of Evolvulus alsinoides Linn. on learning behavior and memory enhancement activity in rodents. Phytother Res 24, 486–493.

132.

Lin

, Chou

, Chen

, Lai

, Lu

, Hao

, Sheen

(2015) A medicinal herb, Melissa officinalis L. ameliorates depressive-like behavior of rats in the forced swimming test via regulating the serotonergic neurotransmitter. J Ethnopharmacol 175, 266–272.

133.

Beheshti

, Shahmoradi

(2018) Therapeutic effect of Melissa officinalis in an amyloid-β rat model of Alzheimer’s disease. J Herbmed Pharmacol 7, 193–199.

134.

Perry

, Bollen

, Perry

, Ballard

(2003) Salvia for dementia therapy: Review of pharmacological activity and pilot tolerability clinical trial. Pharmacol Biochem Behav 75, 651–659.

135.

Rodrigues

, Kanazawa

, das Neves

, da Silva

, Horst

, Pizzolatti

, Santos

, Baggio

, Werner

(2012) Antinociceptive and anti-inflammatory potential of extract and isolated compounds from the leaves of Salvia officinalis in mice. J Ethnopharmacol 139, 519–526.

136.

Ahmed

, Chandra

, Manjunath

(2011) Acetylcholine and memory-enhancing activity of Ficus racemosa bark. Pharmacognosy Res 3, 246–249.

137.

Parle

, Dhingra

, Kulkarni

(2004) Improvement of mouse memory by Myristica fragrans seeds. J Med Food 7, 157–161.

138.

Esfandiary

, Karimipour

, Mardani

, Ghanadian

, Alaei

, Mohammadnejad

, Esmaeili

(2015) Neuroprotective effects of Rosa damascena extract on learning and memory in a rat model of amyloid-beta-induced Alzheimer’s disease. Adv Biomed Res 4, 131.

139.

Homayoun

, Seghatoleslam

, Pourzaki

, Shafieian

, Hosseini

, Ebrahimzadeh Bideskan

(2015) Anticonvulsant and neuroprotective effects of Rosa damascena hydro-alcoholic extract on rat hippocampus. Avicenna J Phytomed 5, 260–270.

140.

Senol

, Orhan

, Kurkcuoglu

, Khan

MTH

, Altintas

, Sener

, Baser

KHC

(2013) A mechanistic investigation on anticholinesterase and antioxidant effects of rose (Rosa damascena Mill.). Food Res Int 53, 502–509.

141.

Aslam

MaS

, N (2015) Vitis vinifera juice ameliorates depression-like behavior in mice by modulating biogenic amine neurotransmitters. Bangladesh J Pharmacol 10, 753–758.

142.

Lakshmi

, Sudhakar

, Anisha

(2014) Neuroprotective role of hydroalcoholic extract of Vitis vinifera against aluminium-induced oxidative stress in rat brain. Neurotoxicology 41, 73–79.

143.

Soheili

, Khalaji

, Mirhashemi

, Salami

(2018) The effect of essential oil of Lavandula angustifolia on amyloid beta polymerization: An in vitro study. Iranian J Chem Chem Eng, 37, 201–207.

144.

Handral

, Pandith

, Shruthi

(2012) A review on Murraya koenigii: Multipotential medicinal plant. Asian J Pharm Clin Res 5, 5–14.

145.

Guaâdaoui

, Bouhtit

, Cherfi

, Hamal

(2015) The preventive approach of biocompounactives (2): A review in recent advances in common fruits. Int J Food Sci Nutr 4, 189–207.

146.

Kulkarni

, Kasture

, Mengi

(2010) Efficacy study of Prunus amygdalus (almond) nuts in scopolamine-induced amnesia in rats. Indian J Pharmacol 42, 168.

147.

Reddy

, Tonk

, Kumar

, Vijayan

, Kandimalla

, Kuruva

, Reddy

(2017) A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer’s disease. Biochem Biophys Res Commun 483, 1156–1165.

148.

Reddy

, Tripathi

, Troung

, Tirumala

, Reddy

, Anekonda

, Shirendeb

, Calkins

, Reddy

, Mao

, Manczak

(2012) Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: Implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta 1822, 639–649.

149.

Reddy

, Beal

(2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14, 45–53.