Phytochemicals mitigate AD mitochondrial dysfunctions: History
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Subjects: Pharmacology & Pharmacy
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Md Ataur Rahman

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive function and neuronal damage. Although the precise pathobiology of AD remains elusive, accumulating evidence suggests that mitochondrial dysfunction is one of the underlying causes of AD. Mutations in mitochondrial or nuclear DNA that encode mitochondrial components may cause mitochondrial dysfunction. In particular, the dysfunction of electron transport chain complexes, along with the interactions of mitochondrial pathological proteins are associated with mitochondrial dysfunction in AD. Mitochondrial dysfunction causes an imbalance in the production of reactive oxygen species, leading to oxidative stress (OS) and vice versa. Neuroin-flammation is another potential contributory factor that induces mitochondrial dysfunction. Phy-tochemicals or other natural compounds have the potential to scavenge oxygen free radicals and enhance cellular antioxidant defense systems, thereby protecting against OS-mediated cellular damage. Phytochemicals can also modulate other cellular processes, including autophagy and mitochondrial biogenesis.

  • Alzheimer’s disease
  • mitochondrial dysfunctions
  • phytochemicals

1. Introduction

Several studies have demonstrated that mitochondrial dysfunction leads to several neurodegenerative diseases, including Alzheimer's disease (AD) [1][2][3]. AD shows common symptoms such as insanity and leads to a morbid state and death in the aged population [4]. In both familial and sporadic patterns, AD is characterized by dual unique medical hallmarks: senile plaques formed via the extracellular accumulation of amyloid-β (Aβ) peptide and intracellular deposition of neurofibrillary tangles (NFTs) formed via hyperphosphorylation of tau proteins [5][6]. These phenomena are accompanied by both pre- and postsynaptic and neuronal casualty [7]; however, the pathogenesis of AD pathogenesis is still unclear. In addition, multiple reports demonstrate that the alterations in axonal transport (AT) are the precise culprit for the development of neurodevelopmental diseases such as AD [8]. AD in mammals involves the atypical decomposition of several abnormal organelles like mitochondria, resulting in the degeneration of senile plaques along with abnormal neuronal expansion leading to a decline in neurites [9]. Phytochemicals or plant-derived chemical compounds are currently under research with unestablished health benefits [10]. Phytochemicals show multiple beneficial effects on mitochondrial dysfunction [11]; however, enough investigations have not been performed yet examining their clinical application.

A wide range of studies have demonstrated that numerous bioactive phytochemicals and other organic compounds may improve the treatment of AD [12]. Phytochemicals, including polyphenolic compounds that are present in numerous plants exhibit several essential properties such as anti-inflammatory potential, DNA repair, autophagy, and antioxidant activities [13]. In the brains of AD patients as well as transgenic AD mouse models, APP and Aβ are present in mitochondrial membranes, interrupting the mitochondrial electron transport system [14]. Potential therapeutic effects of these phytochemicals include antioxidant and anti-inflammatory activities via modulation of Aβ toxicity. Mitochondrial dysfunction discharges excessive quantities of H2O2, which ultimately leads to irreversible cellular dysfunction and damage in the brain [15]. Aggregated Aβ peptides, H2O2-induced hydroxyl radical, and mitochondrial dysfunction caused by APP in AD may restrain in addition to pharmacological approaches using phytochemicals that preserve mitochondrial dynamics [16]. Owing to their therapeutic capabilities, phytobioactive compounds have been deliberated as favorable beneficial agents for AD and age-related diseases [17].

2. Mitochondrial Dysfunction in AD via ROS Production

Oxidative stress (OS) occurs owing to the imbalance between the generation of reactive oxygen species (ROS) and cellular antioxidant potential. OS stands for excess quantities of ROS production that incur damage to nucleic acids and small molecules such as proteins or lipids. OS can lead to neuronal, specifically causing neurodegenerative diseases and cellular aging processes [18]. Restrained ROS production has physiological roles, particularly in controlling cellular redox equilibrium and regulating intracellular signal transduction [19][20]. ROS (collectively, H2O2, OH, and O2).-) may be the causative factor leading to defects in mitochondrial respiration and the development processes of the human brain that are accompanied by augmented ROS generation. They also contribute to dynamic changes in the brain during AD and aging progression (Figure 1).

The primary origins of ROS production in the brain under functional circumstances as well as in pathological processes (e.g., neurological diseases) are complex I and complex III of the respiratory chain. Complex I discharge superoxide (O2.-) into the intermembrane space such as the matrix, and complex III liberates O2.- to both sides of the electron transport chain (ETC) or inner mitochondrial membrane. Hydrogen peroxide (H2O2) can be generated from O2.- by an enzyme called superoxide dismutase. Both molecules can cross the inner membranes and can produce extremely reactive hydroxyl radical (.OH). Under physiological conditions, the proton movements and the respiratory state of mitochondria produce H2O2 and O2- from the electron transport chain (ETC) [21]. Complex IV also enhances the generation of ROS, whereas complexes III and V generate a minimal amount of ROS [22]. Apart from these, defective production and detoxification of ROS are critically involved in mitochondrial dysfunction [23]. During the aging process, a high amount of ROS is generated due to defective mitochondria. Likewise, a decline in antioxidant enzyme activities ensues, leading to increased ROS production[23][24]. Excess ROS production adversely affects the ETC; complexes I, III, and IV appear to be the most affected, while complex II remains undisturbed [23][25].

Figure 1. Mitochondrial dysfunction and oxidative stress in neurons lead to the development of AD. Typically, ROS are produced via numerous mechanisms such as ER stress, mitochondrial dysfunction, neuroinflammation, and excitotoxicity. Excessive ROS generation leads to oxidative stress (OS), which is responsible for mitochondrial dysfunction. OS prevents the degradation of protein molecules and impairs the clearance of misfolded proteins, which subsequently leads to protein aggregation causing neuronal death and AD.

3. Mitochondrial Deformity as an Outcome of AD Progression

Accumulating evidence has demonstrated that metabolic alterations play a pivotal role in AD progression mediated by several pathogenic factors such as ROS, mitochondrial deformity, and Aβ load [26]. Extensive research has shown that ROS formation mediated by Aβ and calcium imbalance leads to mitochondrial injuries (Figure 2), which are categorized as a secondary mitochondrial failure. Hippocampal expression of mutant APP and Aβ in mouse HT22 cell lines led to impaired mitochondrial dynamics, alterations of mitochondrial structure, and action in neurons [27]. Amyloid precursor proteins (APP) can lead to the overexpression of mitochondrial protein import channels in AD sensitive brain regions, leading to mitochondrial malfunction [28]. Alternatively, several studies have shown that Aβ precisely disorganizes mitochondrial dynamics and hinders critical enzymatic functions. Lustbader et al. reported that Aβ-binding alcohol dehydrogenase (ABAD) directly interacts with Aβ and leads to Aβ-linked apoptosis, mitochondrial toxicity, and free-radical formation in neuronal cells [29]. Furthermore, voltage-dependent anion-selective channel 1 protein (VDAC1) is excessively expressed in AD-vulnerable brains, which combines with phosphorylated tau and Aβ to block mitochondrial intramembranous pores, accelerating mitochondrial impairment [30]. A distinct number of in vitro analysis proposed a connection among augmented Aβ levels, mitochondrial abnormal function, and oxidative burden, collectively leading to AD progression. Nevertheless, the origin of the impairment of mitochondrial dynamics in AD pathogenesis remains elusive.

4. Phytochemicals Prevent Mitochondrial Dysfunction and Improve Biogenesis

Several phytochemicals function to neutralize ROS and activate cellular antioxidant mechanisms. Phytochemicals also enhance mitochondrial biogenesis and protect neurons from toxic damage [31]. Additionally, phytochemicals can stimulate cell survival pathways by triggering many growths signaling pathways. In this section, we discuss recently explored phytochemicals that have been shown to protect neurons from mitochondrial dysfunction in AD by stimulating numerous signaling pathways. Molecular targets, experimental model, research outcomes, and molecular signaling systems of these phytochemicals are summarized in Table 1. Additionally, epidemiological as well as clinical interventions have been displayed that dietary phytochemicals, for example Mediterranean diet, exhibit beneficial properties in dementia patients, AD, PD, depressive disorders, and mild cognitive impairment [32]. Secondary metabolites of phytochemicals from Mediterranean diet contain ω-3 polyunsaturated fatty acids which has been described to maintain cognitive function in human studies [33].

Figure 2. Mitochondrial dysfunction in AD pathogenesis. Aβ and Tau initiate mitochondrial dysfunctions that can result in the modulation of several factors. ROS is generated, which causes lipid peroxidation and DNA damage to initiate apoptosis. Damaged mitochondria demonstrate a decrease in mitochondrial membrane potential (ΔΨm) as a result of the activation of mitochondrial permeability transition pores (mPTPs), which release cytochrome c and apoptosis-inducing factor (AIF), and consequently, initiate apoptosis pathway. Aβ and pTau improve mitochondrial fission and mitophagy.

Anthocyanins control mitochondrial fission/fusion pathways, prevent complex I APP Swedish K670N/M671L double mutation (APPswe), and promote normal mitochondrial dynamics [34]. Numerous phenolic compounds exert neuroprotective effects in AD and other neurodegenerative diseases and. Sulfuretin, a well-known flavonoid glycoside derived from Albizia julibrissin, protects primary hippocampal neuronal cells and SH-SY5Y neuroblastoma cells from Aβ-mediated neurotoxicity [35]. Dietary (poly)phenols have been found to cross blood-brain barrier (BBB) in endothelial cells and shown neuroprotective potential [36]. Polyphenol resveratrol, derived from grapes and black barriers, protects HT22 and PC12 cells against Aβ toxicity by activating the PI3K/Akt/Nrf2 pathway [37]. In addition, resveratrol prevents cell death and represses ROS production induced by Aβ toxicity by enhancing PI3K/Akt phosphorylation, the protein levels of SOD, HO-1, and GSH, and Nrf2 nuclear translocation [38]. Resveratrol also found to cross BBB [39]. Quercetin, a hydroxytyrosol derived from olives, prompts mitochondrial biogenesis and enhances muscle mtDNA in adult men [40]. Tea polyphenols (TPs) mitigate OS in H2O2-induced human neuroblastoma SH-SY5Y cells via Keap1-Nrf2 signaling initiation and decrease in H2O2-mediated cell death, as well as ROS and H2O2 levels to protect against mitochondrial dysfunction [41]. Liquiritigenin prompts mitochondrial fusion and prevents mitochondrial cytotoxicity, in addition to the fragmentation induced by Aβ in SK-N-MC cells [42]. In addition, EGCG and resveratrol increase the levels of Sirt-1 and AMPK along with mitochondrial biogenesis via PGC-1α, thereby protecting the neuronal cells [43]. Conversely, kaempferol, resveratrol luteolin, wogonin, quercetin, theaflavins, EGCG, curcumin, and baicalein open the mPTP, which activates the apoptosis pathway in cancer cells via Bcl-2 and Bcl-xL inhibition along with oligomerization of Bax, in addition to the downregulation of NF-κB signaling pathway [44]. Additionally, curcumin has been found to cross BBB to enter brain tissue and considerable exhibited neuro-protective as well as anti-cancer properties [45]. A previous study showed that curcumin protected against mitochondrial degeneration by mitigating the autophagic pathway via modulation of the PI3K/Akt/mTOR pathway in the ischemia/reperfusion-induced rat model [46]. Kaempferol passed to penetrate BBB and attenuates neuroinflammation as well as BBB dysfunction in cerebral ischemia/reperfusion rats in addition to improve neurological deficits [47]. A ginseng-derived exogenous lysophosphatidic acid receptor ligand, gintonin, improves blood-brain barrier permeability in primary human brain microvascular endothelial cells (HBMECs) [48].

Table 1. Different phytochemicals mitigating mitochondrial dysfunctions in AD pathology.

Phytochemicals

Experimental model

Pathobiology

Research outcomes

Molecular signaling

References

Anthocyanins

APP Swedish K670N/M671L double mutation (APPswe)

Mitochondrial dysfunction and oxidative stress

Ameliorate mitochondrial dysfunction

Increased NADH levels

[34]

Resveratrol

Aβ-induced cytotoxicity in PC12 cells

Oxidative stress

Neuroprotection, Reduction of memory impairment

Reduced ROS, Induced SOD, PI3K, Akt

[49]

Tea polyphenols

SH-SY5Y cells

Oxidative stress

Neuroprotection

Keap1-Nrf2 signaling initiation

[41]

Sulfuretin

Aβ neurotoxicity in primary hippocampal neurons and SH-SY5Y cells

Oxidative stress

Neuroprotection

Activation of Nrf2/HO-1 and PI3K/Akt

[35]

Genistein

Transgenic APP/PS1 rat model of sporadic AD

Impairment of cognition, Increased β-amyloid and hyperphosphorylated tau protein

Improved learning and memory recognition,

Inhibition of apoptosis and antioxidant functions

PPARγ-mediated increased release of ApoE,

Autophagy activation and reduction in protein aggregates.

[50][51]

Liquiritigenin

Aβ-induced SK-N-MC cells

Mitochondrial fragmentation

Inhibited mitochondrial fragmentation and cytotoxicity

Mediated by Mfn1, Mfn2, and Opa1 signaling

[42]

Kaempferol

Porcine embryos

Oxidative stress

Prevented mitochondrial membrane potential and ROS generation.

Induced autophagy

[52]

Curcumin

Sprague Dawley male rats

Cerebral Ischemia

Neuroprotection

Autophagy and PI3K/Akt/mTOR pathway

[46]

Epigallocatechin-3-gallate (EGCG)

Rat primary cortical neuron

Pathological tau species

Enhanced tau degradation in an Nrf2-dependent manner

Increase autophagy, tau clearance

[53]

Quercetin

H2O2-induced neurotoxicity in Sprague-Dawley rat

Oxidative stress

Neuroprotection

Increased Aβ clearance

[54]

 

4.1. Phytochemical Intervention of Molecular Signaling Pathways Related to Mitochondrial Dysfunctions in AD

Accumulating evidence has indicated that a large number of phytochemicals are capable of showing numerous benefits against mitochondrial dysfunction in AD pathogenesis by modulating molecular signaling pathways. Several polyphenols promote mitochondrial functions and biogenesis, particularly by regulating ETC activity, redox state modulation, and apoptosis inhibition. Phenolic acids can scavenge peroxynitrite, superoxide, and hydroxyl radicals, terminate radical chain reactions, and upregulate several protective genes that encode extracellular signal-related kinase 1/2 (ERK1/2), heat shock protein 70, and heme oxygenase-1 (HO-1). Several in vivo and in vitro studies have revealed that curcumin can prevent mitochondrial dysfunction in AD by scavenging hydroxyl radicals, hydrogen peroxide, and peroxynitrite and attenuating lipid peroxidation [55]. Flavonoids exhibit antioxidant activity and protect neurons via modulation of cellular signaling pathways, in addition to the induction of expression of several genes [56]. Flavonoids can also increase the expression of ROS-eliminating enzymes such as catalase, SOD, and glutathione reductase via the activation of the Keap1/Nrf2/ARE-mediated signaling pathway [57]. Polyphenols such as catechin, apigenin, luteolin, kaempferol, curcumin, and quercetin can inhibit ROS-generating xanthine oxidase (XO), NADPH oxidase (NOX), and MAO [58][59].

Flavonoids exert neuronal effects via several lipid kinase and protein kinase signaling pathways, such as the protein kinase C, MAPK tyrosine kinase, PI3K/Akt signaling pathways, and NF-κB pathway [60]. The stimulatory or inhibitory properties of these pathways can significantly modulate gene expression by altering the phosphorylation state as well as affecting the neuronal properties and function of target molecules. As a result, this might lead to synaptic protein synthesis, morphological variations, and plasticity involved in neurodegenerative processes in AD. Serine/threonine kinases, known as MAPK and mitogen-activated kinases, regulate numerous cellular functions via extracellular signal transduction pathways, generating intracellular downstream signals [61]. Flavonoids have selectively interacted with MAPK kinases, including ERK, MEK1, and MEK2 signaling, resulting in the activation of downstream cAMP response element-binding protein (CREB) [62]. These results might lead to alterations in memory function and synaptic plasticity via the upregulation of neuroprotective pathways in AD.

Blueberry supplementation rich in anthocyanins and flavonols increased memory performance in rats via CREB activation and promoting pro-BDNF and mature BDNF levels in the hippocampus [63]. In another study, 12 weeks of blueberry supplementation activated Akt phosphorylation, mTOR downstream activation, and enhanced activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) expression in the hippocampus of aged animals [63]. This might promote morphology and spine density in neuronal cells, thereby enhancing learning and memory function. In addition, treatment with green tea catechins ameliorated memory impairments and promoted spatial learning function by diminishing the oligomers of Aβ (1–42) in senescence-accelerated mice by augmenting the expression of the PKA/CREB pathway in the hippocampus [64]. Furthermore, EGCG promoted ERK and PI3K-mediated phosphorylation of CREB as well as stimulated GluR2 levels and modulated synaptogenesis, neurotransmission activity, and plasticity in cortical neurons [65]. In addition, flavonoids modulate the activity of PI3K via direct interactions with its ATP binding site [66]. Hesperetin is an activator of the Akt/PKB pathway in cortical neurons. In contrast, quercetin inhibits the prosurvival Akt/PKB pathways by preventing the activity of PI3K [67].

Flavonoids prevent certain activities of CDK5/p25 and GSK-3β, which contribute to the hyperphosphorylation of Tau and accumulation of neurofibrillary tangles in AD pathogenesis [62]. Indirubins prevent CDK5/p25 and GSK-3β and inhibit abnormal phosphorylation of tau in AD pathogenesis [68]. Likewise, GSK-3β activity is inhibited by flavonoid morin [69]. Morin can prevent GSK-3β-mediated phosphorylation of tau in vitro, decrease Aβ-induced tau phosphorylation, and protect against Aβ cytotoxicity in human SH-SY5Y neuroblastoma cells [69]. Furthermore, morin reduces the hyperphosphorylation of tau in the hippocampal neurons of 3xTg-AD mice [69]. Luteolin reduces soluble Aβ, interrupted the PS1-APP association, and diminished GSK-3 activity in an AD mouse model of Tg2576, and rescued cognitive impairments [70].

4.2. Phytochemicals Inhibit AD Specific Protein Aggregation

Neuropathological characteristics of AD involve the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuronal loss in the limbic neocortical brain regions [71]. Pathobiology of AD encompasses oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, reduced neurotrophic factors and neurogenesis, loss of the cholinergic system, autophagy dysfunction, and glutamatergic excitotoxicity [72][73]. Various phytochemicals, anti-inflammatory medications, and antioxidants prevent amyloidogenic monomer synthesis, fibrillar aggregates, and oligomeric formation [74]. Phytochemicals also stimulate nontoxic aggregate formation and proteolytic system activation to ameliorate neuronal mitochondrial dysfunction triggered by Aβ [75]. It is well known that amyloidogenic Aβ 40–42 is produced via consecutive APP cleavage mediated by β-secretase (BACE1) and γ-secretase enzymes [76]. Tannic acid, genistein, ferulic acid, nobiletin, galangin, sinensetin, and tangeretin inhibit β-secretase activity, in addition to behavioral enhancement in AD animal models. In addition, resveratrol, EGCG, icariin, quercetin, luteolin, 7,8-dihydroxyflavine, rutin, and curcumin decrease β-secretase expression and protect neurons [77]. Furthermore, curcumin, oleuropein, genistein, and EGCG promote APP cleavage via α-secretase, producing nontoxic N-terminal soluble APPα product and C-terminal α fragment [78]. Phytochemicals promote α-secretase or prevent β-secretase activity and inhibit fibril and toxic oligomer production. Curcumin as well as other polyphenolic compounds have been changed to mature Aβ aggregates, which make nontoxic molecules as well.

Many phytochemicals inhibit mTOR signaling, thereby inducing the autophagy pathway [79]. Polyphenols inhibit oligomer synthesis and formation, in addition to preventing tau hyperphosphorylation and aggregation reduction under in vitro and in vivo conditions [80]. Soluble Aβ oligomers along with profibrillar species are produced via the action of rosmarinic acid, myricetin, and curcumin, which reduce the number of toxic oligomers and fibrils [81][82]. Aβ aggregation is inhibited by honokiol, myricetin, and luteolin upon binding to the hydrophobic site of the amyloid pentamer and employed the most prominent Aβ1-42 aggregate inhibition in PC12 cells to protect anti-aggregative properties as well as neuronal toxicity [83]. Numerous phytochemicals involved in the pathogenesis of AD are indicated in Figure 3. Another potential benefit of phytochemicals in AD may include their potential role in tau phosphorylation. Tau oligomers are toxic and cause synaptic dysfunction in AD. Several findings have revealed that hyperphosphorylation of tau can be inhibited by treatment with caffeic acid, altenusin, EGCG, curcumin, and resveratrol [84][85]. Moreover, EGCG inhibits the conversion of tau aggregates into toxic oligomers [86]. In addition, emodin and daunorubicin repress tau aggregation and dissolve paired helical filaments under in vitro conditions [87]. In another study, epicatechin-5-gallate and myrecetin were shown to hinder heparin-mediated tau formation, and EGCG administration in an AD transgenic mouse model controlled the phosphorylation of sarkosyl-soluble tau isoform [88][89].

Figure 3. Phytochemicals modulate AD pathogenesis. Phytochemicals stimulate α-secretase activity or may hinder β-secretase activity that inhibits toxic oligomer production. Polyphenols and other compounds modify Aβ aggregates and convert them into nontoxic oligomers. Some phytochemicals inactivate mTOR and initiate the autophagy pathway. Polyphenols and other compounds prevent tau hyperphosphorylation and convert tau aggregates into nontoxic aggregates.

This entry is adapted from the peer-reviewed paper 10.3390/antiox10010023

References

  1. Carvalho, C.; Correia, S.C.; Cardoso, S.; Plácido, A.I.; Candeias, E.; Duarte, A.I.; Moreira, P. The role of mitochondrial dis-turbances in Alzheimer, Parkinson and Huntington diseases. Expert Rev. Neurother. 2015, 15, 867–884, doi:10.1586/14737175.2015.1058160.
  2. Correia, S.C.; Santos, R.X.; Cardoso, S.; Carvalho, C.; Candeias, E.; Duarte, A.I.; Plácido, A.I.; Santos, M.S.; Moreira, P.I. Alzheimer disease as a vascular disorder: Where do mitochondria fit? Exp. Gerontol. 2012, 47, 878–886, doi:10.1016/j.exger.2012.07.006.
  3. Rahman, A.; Rhim, A.H. Therapeutic implication of autophagy in neurodegenerative diseases. BMB Rep. 2017, 50, 345–354, doi:10.5483/bmbrep.2017.50.7.069.
  4. Querfurth, H.W.; LaFerla, F.M. Alzheimer’s Disease. N. Engl. J. Med. 2010, 362, 329–344, doi:10.1056/nejmra0909142.
  5. Uddin, S.; Al Mamun, A.; Rahman, A.; Behl, T.; Perveen, A.; Hafeez, A.; Bin-Jumah, M.N.; Abdel-Daim, M.M.; Ashraf, G.M. Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer’s Disease. Curr. Top. Med. Chem. 2020, 20, 2380–2390, doi:10.2174/1568026620666200601161703.
  6. Uddin, S.; Rahman, A.; Kabir, T.; Behl, T.; Mathew, B.; Perveen, A.; Barreto, G.; Bin‐Jumah, M.N.; Abdel‐Daim, M.M.; Ashraf, G.M. Multifarious roles of mTOR signaling in cognitive aging and cerebrovascular dysfunction of Alzheimer’s disease. IUBMB Life 2020, 72, 1843–1855, doi:10.1002/iub.2324.
  7. Braak, H.; Del Tredici, K. Alzheimer’s pathogenesis: Is there neuron-to-neuron propagation? Acta Neuropathol. 2011, 121, 589–595, doi:10.1007/s00401-011-0825-z.
  8. Wang, Z.-X.; Tan, L.; Yu, J.-T. Axonal Transport Defects in Alzheimer’s Disease. Mol. Neurobiol. 2015, 51, 1309–1321, doi:10.1007/s12035-014-8810-x.
  9. Stokin, G.B.; Lillo, C.; Falzone, T.L.; Brusch, R.G.; Rockenstein, E.; Mount, S.L.; Raman, R.; Davies, P.; Masliah, E.; Williams, D.S.; et al. Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer’s Disease. Sci. 2005, 307, 1282–1288, doi:10.1126/science.1105681.
  10. Vaiserman, A.; Koliada, A.; Lushchak, O. Neuroinflammation in pathogenesis of Alzheimer’s disease: Phytochemicals as potential therapeutics. Mech. Ageing Dev. 2020, 189, doi:10.1016/j.mad.2020.111259.
  11. Naoi, M.; Wu, Y.; Shamoto-Nagai, M.; Maruyama, W. Mitochondria in Neuroprotection by Phytochemicals: Bioactive Poly-phenols Modulate Mitochondrial Apoptosis System, Function and Structure. Int. J. Mol. Sci. 2019, 20, 2451, doi:10.3390/ijms20102451.
  12. Martel, J.; Ojcius, D.M.; Ko, Y.-F.; Ke, P.-Y.; Wu, C.-Y.; Peng, H.-H.; Young, J.D. Hormetic Effects of Phytochemicals on Health and Longevity. Trends Endocrinol. Metab. 2019, 30, 335–346, doi:10.1016/j.tem.2019.04.001.
  13. Franco, R.; Navarro, G.; Martinez-Pinilla, E. Hormetic and Mitochondria-Related Mechanisms of Antioxidant Action of Phy-tochemicals. Antioxidants 2019, 8, 373, doi:10.3390/antiox8090373.
  14. Reddy, P.H.; Beal, M.F. Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol. Med. 2008, 14, 45–53, doi:10.1016/j.molmed.2007.12.002.
  15. Akbar, M.; Essa, M.M.; Daradkeh, G.; Abdelmegeed, M.A.; Choi, Y.; Mahmood, L.; Song, B.-J. Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress. Brain Res. 2016, 1637, 34–55, doi:10.1016/j.brainres.2016.02.016.
  16. Kim, J.; Lee, H.J.; Lee, K.W. Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J. Neurochem. 2010, 112, 1415–1430, doi:10.1111/j.1471-4159.2009.06562.x.
  17. Martel, J.; Ojcius, D.M.; Ko, Y.-F.; Chang, C.-J.; Young, J.D. Antiaging effects of bioactive molecules isolated from plants and fungi. Med. Res. Rev. 2019, 39, 1515–1552, doi:10.1002/med.21559.
  18. Gilgun-Sherki, Y.; Melamed, E.; Offen, D. Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 2001, 40, 959–975, doi:10.1016/s0028-3908(01)00019-3.
  19. Migdal, C.; Serres, M. Espèces réactives de l’oxygène et stress oxydant. Med. Sci. 2011, 27, 405–412, doi:10.1051/medsci/2011274017.
  20. Hsieh, H.-L.; Yang, C.-M. Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases. BioMed Res. Int. 2013, 2013, 1–18, doi:10.1155/2013/484613.
  21. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2008, 417, 1–13, doi:10.1042/bj20081386.
  22. Hroudová, J.; Fišar, Z. Control mechanisms in mitochondrial oxidative phosphorylation☆. Neural Regen. Res. 2013, 8, 363–375.
  23. Starkov, A. The Role of Mitochondria in Reactive Oxygen Species Metabolism and Signaling. Ann. N. Y. Acad. Sci. 2008, 1147, 37–52, doi:10.1196/annals.1427.015.
  24. Schoenfeld, P.; Wojtczak, L. Fatty acids as modulators of the cellular production of reactive oxygen species. Free. Radic. Biol. Med. 2008, 45, 231–241, doi:10.1016/j.freeradbiomed.2008.04.029.
  25. Boffoli, D.; Scacco, S.; Vergari, R.; Solarino, G.; Santacroce, G.; Papa, S. Decline with age of the respiratory chain activity in human skeletal muscle. Biochim. Biophys. Acta 1994, 1226, 73–82, doi:10.1016/0925-4439(94)90061-2.
  26. Chen, Z.; Zhong, C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies. Prog. Neurobiol. 2013, 108, 21–43, doi:10.1016/j.pneurobio.2013.06.004.
  27. Reddy, P.H.; Yin, X.; Manczak, M.; Kumar, S.; Pradeepkiran, J.A.; Vijayan, M.; Reddy, A.P. Mutant APP and amyloid be-ta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hip-pocampal neurons from Alzheimer’s disease. Hum. Mol. Genet. 2018, 27, 2502–2516, doi:10.1093/hmg/ddy154.
  28. Devi, L.; Prabhu, B.M.; Galati, D.F.; Avadhani, N.G.; Anandatheerthavarada, H.K. Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain is Associated with Mitochondrial Dys-function. J. Neurosci. 2006, 26, 9057–9068, doi:10.1523/jneurosci.1469-06.2006.
  29. Lustbader, J.W.; Cirilli, M.; Lin, C.; Xu, H.W.; Takuma, K.; Wang, N.; Caspersen, C.; Chen, X.; Pollak, S.; Chaney, M.; et al. ABAD Directly Links A to Mitochondrial Toxicity in Alzheimer’s Disease. Science 2004, 304, 448–452, doi:10.1126/science.1091230.
  30. Manczak, M.; Reddy, P.H. Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum. Mol. Genet. 2012, 21, 5131–5146, doi:10.1093/hmg/dds360.
  31. De Oliveira, M.R.; Nabavi, S.M.; Manayi, A.; Daglia, M.; Hajheydari, Z. Resveratrol and the mitochondria: From triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochim. Biophys. Acta 2016, 1860, 727–745, doi:10.1016/j.bbagen.2016.01.017.
  32. Singh, B.; Parsaik, A.K.; Mielke, M.M.; Erwin, P.J.; Knopman, D.S.; Petersen, R.C.; Roberts, R.O. Association of Mediterrane-an Diet with Mild Cognitive Impairment and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. J. Alzheimer’s Dis. 2014, 39, 271–282, doi:10.3233/jad-130830.
  33. Román, G.; Jackson, R.; Gadhia, R.; Román, A.; Reis, J. Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease. Rev. Neurol. 2019, 175, 724–741, doi:10.1016/j.neurol.2019.08.005.
  34. Parrado-Fernández, C.; Sandebring-Matton, A.; Rodriguez-Rodriguez, P.; Aarsland, D.; Cedazo-Minguez, A. Anthocyanins protect from complex I inhibition and APPswe mutation through modulation of the mitochondrial fission/fusion pathways. Biochim. Biophys. Acta 2016, 1862, 2110–2118, doi:10.1016/j.bbadis.2016.08.002.
  35. Kwon, S.-H.; Ma, S.-X.; Hwang, J.-Y.; Lee, S.-Y.; Jang, C.-G. Involvement of the Nrf2/HO-1 signaling pathway in sul-furetin-induced protection against amyloid beta25–35 neurotoxicity. Neuroscience 2015, 304, 14–28, doi:10.1016/j.neuroscience.2015.07.030.
  36. Figueira, I.; Garcia, G.; Pimpão, R.C.; Terrasso, A.P.; Costa, I.; Almeida, A.F.; Tavares, L.; Pais, T.F.; Pinto, P.; Ventura, M.R.; et al. Polyphenols journey through blood-brain barrier towards neuronal protection. Sci. Rep. 2017, 7, 1–16, doi:10.1038/s41598-017-11512-6.
  37. Ali, T.; Kim, T.; Rehman, S.U.; Khan, M.S.; Amin, F.U.; Khan, M.; Ikram, M.; Kim, M.O. Natural Dietary Supplementation of Anthocyanins via PI3K/Akt/Nrf2/HO-1 Pathways Mitigate Oxidative Stress, Neurodegeneration, and Memory Impairment in a Mouse Model of Alzheimer’s Disease. Mol. Neurobiol. 2018, 55, 6076–6093, doi:10.1007/s12035-017-0798-6.
  38. Hui, Y.; Chengyong, T.; Cheng, L.; Haixia, H.; Yuanda, Z.; Weihua, Y. Resveratrol Attenuates the Cytotoxicity Induced by Amyloid-β1–42 in PC12 Cells by Upregulating Heme Oxygenase-1 via the PI3K/Akt/Nrf2 Pathway. Neurochem. Res. 2017, 43, 297–305, doi:10.1007/s11064-017-2421-7.
  39. Kaisar, M.A.; Prasad, S.; Cucullo, L. Protecting the BBB endothelium against cigarette smoke-induced oxidative stress using popular antioxidants: Are they really beneficial? Brain Res. 2015, 1627, 90–100, doi:10.1016/j.brainres.2015.09.018.
  40. Nieman, D.C.; Williams, A.S.; Shanely, R.A.; Jin, F.; McAnulty, S.R.; Triplett, N.T.; Austin, M.D.; Henson, D.A. Quercetin’s Influence on Exercise Performance and Muscle Mitochondrial Biogenesis. Med. Sci. Sports Exerc. 2010, 42, 338–345, doi:10.1249/mss.0b013e3181b18fa3.
  41. Qi, G.; Mi, Y.; Wang, Y.; Li, R.; Huang, S.; Li, X.; Liu, X. Neuroprotective action of tea polyphenols on oxidative stress-induced apoptosis through the activation of the TrkB/CREB/BDNF pathway and Keap1/Nrf2 signaling pathway in SH-SY5Y cells and mice brain. Food Funct. 2017, 8, 4421–4432, doi:10.1039/c7fo00991g.
  42. Jo, D.S.; Shin, D.W.; Park, S.J.; Bae, J.-E.; Kim, J.B.; Park, N.Y.; Kim, J.-S.; Oh, J.S.; Shin, J.-W.; Cho, D.-H. Attenuation of Aβ toxicity by promotion of mitochondrial fusion in neuroblastoma cells by liquiritigenin. Arch. Pharmacal Res. 2016, 39, 1137–1143, doi:10.1007/s12272-016-0780-2.
  43. Sandoval-Acuña, C.; Ferreira, J.; Speisky, H. Polyphenols and mitochondria: An update on their increasingly emerging ROS-scavenging independent actions. Arch. Biochem. Biophys. 2014, 559, 75–90, doi:10.1016/j.abb.2014.05.017.
  44. Gorlach, S.; Fichna, J.; Lewandowska, U. Polyphenols as mitochondria-targeted anticancer drugs. Cancer Lett. 2015, 366, 141–149, doi:10.1016/j.canlet.2015.07.004.
  45. Tsai, Y.-M.; Chien, C.-F.; Lin, L.-C.; Tsai, T.-H. Curcumin and its nano-formulation: The kinetics of tissue distribution and blood–brain barrier penetration. Int. J. Pharm. 2011, 416, 331–338, doi:10.1016/j.ijpharm.2011.06.030.
  46. Huang, L.; Chen, C.; Zhang, X.; Lifa, H.; Chen, Z.; Yang, C.; Liang, X.; Zhu, G.; Xu, Z. Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation. J. Mol. Neurosci. 2018, 64, 129–139, doi:10.1007/s12031-017-1006-x.
  47. Li, W.-H.; Cheng, X.; Yang, Y.-L.; Liu, M.; Zhang, S.-S.; Wang, Y.-H.; Du, G.-H. Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats. Brain Res. 2019, 1722, 146361, doi:10.1016/j.brainres.2019.146361.
  48. Kim, D.-G.; Jang, M.; Choi, S.-H.; Kim, H.-J.; Jhun, H.; Kim, H.-C.; Rhim, H.; Cho, I.-H.; Nah, S.-Y. Gintonin, a gin-seng-derived exogenous lysophosphatidic acid receptor ligand, enhances blood-brain barrier permeability and brain delivery. Int. J. Biol. Macromol. 2018, 114, 1325–1337, doi:10.1016/j.ijbiomac.2018.03.158.
  49. Sousa, J.C.; Santana, A.C.F.; Magalhães, G.J.P. Resveratrol in Alzheimer’s disease: A review of pathophysiology and thera-peutic potential. Arquivos Neuro-Psiquiatria 2020, 78, 501, doi:10.1590/0004-282x20200010.
  50. Vallés, S.L.; Dolz-Gaiton, P.; Gambini, J.; Borrás, C.; Lloret, A.; Pallardo, F.V.; Viña, J. Estradiol or genistein prevent Alz-heimer’s disease-associated inflammation correlating with an increase PPARγ expression in cultured astrocytes. Brain Res. 2010, 1312, 138–144, doi:10.1016/j.brainres.2009.11.044.
  51. Pierzynowska, K.; Podlacha, M.; Gaffke, L.; Majkutewicz, I.; Mantej, J.; Węgrzyn, A.; Osiadły, M.; Myślińska, D.; Węgrzyn, G. Autophagy-dependent mechanism of genistein-mediated elimination of behavioral and biochemical defects in the rat model of sporadic Alzheimer’s disease. Neuropharmacology 2019, 148, 332–346, doi:10.1016/j.neuropharm.2019.01.030.
  52. Yao, X.; Jiang, H.; NanXu, Y.; Piao, X.; Gao, Q.; Kim, N. Kaempferol attenuates mitochondrial dysfunction and oxidative stress induced by H2O2 during porcine embryonic development. Theriogenology 2019, 135, 174–180, doi:10.1016/j.theriogenology.2019.06.013.
  53. Chesser, A.S.; Ganeshan, V.; Yang, J.; Johnson, G.V.W. Epigallocatechin-3-gallate enhances clearance of phosphorylated tau in primary neurons. Nutr. Neurosci. 2015, 19, 21–31, doi:10.1179/1476830515y.0000000038.
  54. Godoy, J.A.; Lindsay, C.B.; Quintanilla, R.A.; Carvajal, F.J.; Cerpa, W.; Inestrosa, N.C. Quercetin Exerts Differential Neuro-protective Effects Against H2O2 and Aβ Aggregates in Hippocampal Neurons: The Role of Mitochondria. Mol. Neurobiol. 2017, 54, 7116–7128, doi:10.1007/s12035-016-0203-x.
  55. Barzegar, A.; Moosavi-Movahedi, A.A. Intracellular ROS Protection Efficiency and Free Radical-Scavenging Activity of Curcumin. PLoS ONE 2011, 6, e26012, doi:10.1371/journal.pone.0026012.
  56. Mansuri, M.L.; Parihar, P.; Solanki, I.; Parihar, M.S. Flavonoids in modulation of cell survival signalling pathways. Genes Nutr. 2014, 9, 1–9, doi:10.1007/s12263-014-0400-z.
  57. Tu, W.; Wang, H.; Li, S.; Liu, Q.; Sha, H. The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases. Aging Dis. 2019, 10, 637–651, doi:10.14336/ad.2018.0513.
  58. Carradori, S.; Gidaro, M.C.; Petzer, A.; Costa, G.; Guglielmi, P.; Chimenti, P.; Alcaro, S.; Petzer, J.P. Inhibition of Human Monoamine Oxidase: Biological and Molecular Modeling Studies on Selected Natural Flavonoids. J. Agric. Food Chem. 2016, 64, 9004–9011, doi:10.1021/acs.jafc.6b03529.
  59. Malik, N.; Dhiman, P.; Sobarzo-Sanchez, E.; Khatkar, A. Flavonoids and Anthranquinones as Xanthine Oxidase and Mon-oamine Oxidase Inhibitors: A New Approach Towards Inflammation and Oxidative Stress. Curr. Top. Med. Chem. 2019, 18, 2154–2164, doi:10.2174/1568026619666181120143050.
  60. Spencer, J.P. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr. 2007, 2, 257–273, doi:10.1007/s12263-007-0056-z.
  61. Cargnello, M.; Roux, P.P. Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases. Microbiol. Mol. Biol. Rev. 2012, 76, 496, doi:10.1128/mmbr.00013-12.
  62. Baptista, F.I.; Henriques, A.G.; Silva, A.M.S.; Wiltfang, J.; Silva, O.A.B.D.C.E. Flavonoids as Therapeutic Compounds Tar-geting Key Proteins Involved in Alzheimer’s Disease. ACS Chem. Neurosci. 2014, 5, 83–92, doi:10.1021/cn400213r.
  63. Williams, C.M.; El Mohsen, M.A.; Vauzour, D.; Rendeiro, C.; Butler, L.T.; Ellis, J.A.; Whiteman, M.; Spencer, J.P. Blueber-ry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free. Radic. Biol. Med. 2008, 45, 295–305, doi:10.1016/j.freeradbiomed.2008.04.008.
  64. Onishi, S.; Meguro, S.; Pervin, M.; Kitazawa, H.; Yoto, A.; Ishino, M.; Shimba, Y.; Mochizuki, Y.; Miura, S.; Tokimitsu, I.; et al. Green Tea Extracts Attenuate Brain Dysfunction in High-Fat-Diet-Fed SAMP8 Mice. Nutrients 2019, 11, 821, doi:10.3390/nu11040821.
  65. Schroeter, H.; Bahia, P.; Spencer, J.P.E.; Sheppard, O.; Rattray, M.; Cadenas, E.; Rice-Evans, C.; Williams, R.J. (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. J. Neurochem. 2007, 101, 1596–1606, doi:10.1111/j.1471-4159.2006.04434.x.
  66. Rebas, E.; Rzajew, J.; Radzik, T.; Zylinska, L. Neuroprotective Polyphenols: A Modulatory Action on Neurotransmitter Pathways. Curr. Neuropharmacol. 2020, 18, 431–445, doi:10.2174/1570159x18666200106155127.
  67. Khan, A.; Jahan, S.; Imtiyaz, Z.; Alshahrani, S.; Makeen, H.A.; AlShehri, B.M.; Kumar, A.; Arafah, A.; Rehman, M. Neuro-protection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals. Biomedicines 2020, 8, 284, doi:10.3390/biomedicines8080284.
  68. Hasan, G.M.; Hassan, I. Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer’s Disease. Curr. Top. Med. Chem. 2020, 20, 1059–1073, doi:10.2174/1568026620666200106125910.
  69. Gong, E.J.; Park, H.R.; Kim, M.E.; Piao, S.; Lee, E.; Jo, D.-G.; Chung, H.Y.; Ha, N.-C.; Mattson, M.P.; Lee, J. Morin attenuates tau hyperphosphorylation by inhibiting GSK3β. Neurobiol. Dis. 2011, 44, 223–230, doi:10.1016/j.nbd.2011.07.005.
  70. Llorens-Marítin, M.; Jurado, J.; Hernã¡ndez, F.; Ávila, J. GSK-3β, a pivotal kinase in Alzheimer disease. Front. Mol. Neurosci. 2014, 7, 46, doi:10.3389/fnmol.2014.00046.
  71. King, A.; Bodi, I.; Troakes, C. The Neuropathological Diagnosis of Alzheimer’s Disease—The Challenges of Pathological Mimics and Concomitant Pathology. Brain Sci. 2020, 10, 479, doi:10.3390/brainsci10080479.
  72. Farkhondeh, T.; Samarghandian, S.; Pourbagher-Shahri, A.M.; Sedaghat, M. The impact of curcumin and its modified for-mulations on Alzheimer’s disease. J. Cell. Physiol. 2019, 234, 16953–16965, doi:10.1002/jcp.28411.
  73. Michalska, P.; León, R. When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflamma-tion Induce Neurodegeneration. Antioxidants 2020, 9, 740, doi:10.3390/antiox9080740.
  74. Henríquez, G.; Gomez, A.; Guerrero, E.D.; Narayan, M. Potential Role of Natural Polyphenols against Protein Aggregation Toxicity: In Vitro, In Vivo, and Clinical Studies. ACS Chem. Neurosci. 2020, 11, 2915–2934, doi:10.1021/acschemneuro.0c00381.
  75. Carmona, V.; Martín-Aragón, S.; Goldberg, J.; Schubert, D.; Bescós, P.B. Several targets involved in Alzheimer’s disease am-yloidogenesis are affected by morin and isoquercitrin. Nutr. Neurosci. 2018, 23, 575–590, doi:10.1080/1028415x.2018.1534793.
  76. Rahman, M.A.; Rahman, M.S.; Uddin, M.J.; Mamum-Or-Rashid, A.N.M.; Pang, M.G.; Rhim, H. Emerging risk of environ-mental factors: Insight mechanisms of Alzheimer’s diseases. Environ. Sci. Pollut. R 2020, 27, 44659–44672.
  77. Cione, E.; La Torre, C.; Cannataro, R.; Caroleo, M.C.; Plastina, P.; Gallelli, L. Quercetin, Epigallocatechin Gallate, Curcumin, and Resveratrol: From Dietary Sources to Human MicroRNA Modulation. Molecules 2019, 25, 63, doi:10.3390/molecules25010063.
  78. Haass, C.; Kaether, C.; Thinakaran, G.; Sisodia, S. Trafficking and Proteolytic Processing of APP. Cold Spring Harb. Perspect. Med. 2012, 2, a006270, doi:10.1101/cshperspect.a006270.
  79. Rahman, A.; Hwang, H.; Nah, S.-Y.; Rhim, H. Gintonin stimulates autophagic flux in primary cortical astrocytes. J. Ginseng Res. 2018, 44, 67–78, doi:10.1016/j.jgr.2018.08.004.
  80. Zheng, Q.; Kebede, M.T.; Kemeh, M.M.; Islam, S.; Lee, B.; Bleck, S.D.; Wurfl, L.A.; Lazo, N.D. Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies. Molecules 2019, 24, 2316, doi:10.3390/molecules24122316.
  81. Ono, K.; Li, L.; Takamura, Y.; Yoshiike, Y.; Zhu, L.; Han, F.; Mao, X.; Ikeda, T.; Takasaki, J.-I.; Nishijo, H.; et al. Phenolic Compounds Prevent Amyloid β-Protein Oligomerization and Synaptic Dysfunction by Site-specific Binding. J. Biol. Chem. 2012, 287, 14631–14643, doi:10.1074/jbc.m111.325456.
  82. Thapa, A.; Jett, S.D.; Chi, E.Y. Curcumin Attenuates Amyloid-β Aggregate Toxicity and Modulates Amyloid-β Aggregation Pathway. ACS Chem. Neurosci. 2015, 7, 56–68, doi:10.1021/acschemneuro.5b00214.
  83. Das, S.; Stark, L.; Musgrave, I.F.; Pukala, T.L.; Smid, S. Bioactive polyphenol interactions with β amyloid: A comparison of binding modelling, effects on fibril and aggregate formation and neuroprotective capacity. Food Funct. 2016, 7, 1138–1146, doi:10.1039/c5fo01281c.
  84. Patil, S.P.; Tran, N.; Geekiyanage, H.; Liu, L.; Chan, C. Curcumin-induced upregulation of the anti-tau cochaperone BAG2 in primary rat cortical neurons. Neurosci. Lett. 2013, 554, 121–125, doi:10.1016/j.neulet.2013.09.008.
  85. Chua, S.W.; Cornejo, A.; Van Eersel, J.; Stevens, C.H.; Vaca, I.; Cueto, M.; Kassiou, M.; Gladbach, A.; Macmillan, A.; Lewis, L.; et al. The Polyphenol Altenusin Inhibits in Vitro Fibrillization of Tau and Reduces Induced Tau Pathology in Primary Neurons. ACS Chem. Neurosci. 2017, 8, 743–751, doi:10.1021/acschemneuro.6b00433.
  86. Sonawane, S.K.; Chidambaram, H.; Boral, D.; Gorantla, N.V.; Balmik, A.A.; Dangi, A.; Ramasamy, S.; Marelli, U.K.; Chin-nathambi, S. EGCG impedes human Tau aggregation and interacts with Tau. Sci. Rep. 2020, 10, 12579, doi:10.1038/s41598-020-69429-6.
  87. Pickhardt, M.; Gazova, Z.; Von Bergen, M.; Khlistunova, I.; Wang, Y.; Hascher, A.; Mandelkow, E.-M.; Biernat, J.; Mandel-kow, E. Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer’s Paired Helical Filamentsin Vitroand in Cells. J. Biol. Chem. 2004, 280, 3628–3635, doi:10.1074/jbc.m410984200.
  88. Taniguchi, S.; Suzuki, N.; Masuda, M.; Hisanaga, S.-I.; Iwatsubo, T.; Goedert, M.; Hasegawa, M. Inhibition of Hepa-rin-induced Tau Filament Formation by Phenothiazines, Polyphenols, and Porphyrins. J. Biol. Chem. 2004, 280, 7614–7623, doi:10.1074/jbc.m408714200.
  89. Rezai-Zadeh, K.; Arendash, G.W.; Hou, H.; Fernandez, F.; Jensen, M.; Runfeldt, M.; Shytle, R.D.; Tan, J. Green tea epigallo-catechin-3-gallate (EGCG) reduces β-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res. 2008, 1214, 177–187, doi:10.1016/j.brainres.2008.02.107.
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