Polyherbal and Multimodal Treatments: Kaempferol- and Quercetin-Rich Herbs Alleviate Symptoms of Alzheimer’s Disease

Simple Summary Despite the well-documented pathophysiology of Alzheimer’s Disease (AD), treatment options are limited in diversity and efficacy. Thus, the development of new treatments requires an extensive understanding of molecular pathways altered by drugs in development. In this review, we survey the literature regarding common herbal phytochemicals, kaempferol and quercetin, with a specific focus on their multiple mechanisms that alleviate the pathological underpinnings of AD. Here, we utilize the well-documented mechanisms of quercetin to propose a novel multimodal mechanism of kaempferol, and we discuss common herbal sources and the limitations of these potential treatments. Abstract Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder impairing cognition and memory in the elderly. This disorder has a complex etiology, including senile plaque and neurofibrillary tangle formation, neuroinflammation, oxidative stress, and damaged neuroplasticity. Current treatment options are limited, so alternative treatments such as herbal medicine could suppress symptoms while slowing cognitive decline. We followed PRISMA guidelines to identify potential herbal treatments, their associated medicinal phytochemicals, and the potential mechanisms of these treatments. Common herbs, including Ginkgo biloba, Camellia sinensis, Glycyrrhiza uralensis, Cyperus rotundus, and Buplerum falcatum, produced promising pre-clinical results. These herbs are rich in kaempferol and quercetin, flavonoids with a polyphenolic structure that facilitate multiple mechanisms of action. These mechanisms include the inhibition of Aβ plaque formation, a reduction in tau hyperphosphorylation, the suppression of oxidative stress, and the modulation of BDNF and PI3K/AKT pathways. Using pre-clinical findings from quercetin research and the comparatively limited data on kaempferol, we proposed that kaempferol ameliorates the neuroinflammatory state, maintains proper cellular function, and restores pro-neuroplastic signaling. In this review, we discuss the anti-AD mechanisms of quercetin and kaempferol and their limitations, and we suggest a potential alternative treatment for AD. Our findings lead us to conclude that a polyherbal kaempferol- and quercetin-rich cocktail could treat AD-related brain damage.


Introduction
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory impairment.AD could affect 152 million individuals by 2050 [1].The progression of AD is influenced by multiple factors, including the accumulation of beta-amyloid plaques (Aβ) and the formation of neurofibrillary tangles (NFTs).The aggregation of Aβ plaques exacerbates the disease by impairing neuronal function and triggering neuroinflammation [2][3][4][5].Oxidative stress and the presence of neurofibrillary
The anti-Aβ effects of quercetin are well studied in AD and related models and have yielded promising therapeutic properties.The hydrophobic groups of quercetin can inhibit the formation of Aβ fibrils [120][121][122][123]156].Chronic quercetin treatment also slowed Aβ aggregation by potentiating AMPK signaling and inhibiting mitochondrial ROS production, leading to improved memory and object recognition in APPswe/PS1dE9 [80,157].Quercetin treatment also inhibits the BACE1-mediated cleavage of APP into Aβ by inhibiting NF-kB [74].Consequently, mitochondrial membrane permeability is restored, and cellular survival is favored over oxidative stress [158].This anti-neurodegenerative effect could be due to the free radical-quenching structure of the catechol group, reducing neuroinflammation, lipid peroxidation, mitochondrial stress, and DNA damage [38,51].Elevated SOD, GPx, and Na + -K + ATPase activity could also be due to quercetin's anti-Aβ effects [44,78].
In many studies, quercetin and its derivatives reduced tau hyperphosphorylation [23,58,132,159].In rodent HT22 hippocampal neurons, chronic quercetin treatment inhibited tau phosphorylation at four sites by reducing p-Cdk5 levels, limiting calpain activity, and dramatically reducing Ca 2+ influx [58].In 3xTgAD mice, chronic quercetin inhibited Aβ pathology, reduced NFT levels, and prevented astrocytic and microglial hyperactivity in the amygdala and hippocampus [132,160], showing that the anti-Aβ and anti-tau mechanisms of quercetin depend on its anti-inflammatory effects.Consequently, these mice demonstrated improved learning and memory and decreased anxiety [132], while combined exercise and quercetin treatment robustly improved spatial memory in AD rodents [161].Studies also found that quercetin enhanced cell viability and morphology by reducing MDA and ROS levels and increasing antioxidant SOD and GSH activity [159,162], limiting NF-κB signaling, restoring mitochondrial membrane potential to baseline, inhibiting tau hyperphosphorylation, and regulating Akt/PI3K/GSK-3β signaling pathway [159,163].Taken together, these data show that quercetin has a multimodal mechanism of action in treating AD.Of note, the anti-tau and consequent pro-neuroplastic effect of quercetin is further explored in Section 5, but the primary anti-inflammatory, anti-Aβ, ant-tau, and pro-neuroplastic effects of this flavonoid are all dependent on each other.
In many studies, quercetin and its derivatives reduced tau hyperphosphorylation [23,58,132,159].In rodent HT22 hippocampal neurons, chronic quercetin treatment inhibited tau phosphorylation at four sites by reducing p-Cdk5 levels, limiting calpain activity, and dramatically reducing Ca 2+ influx [58].In 3xTgAD mice, chronic quercetin inhibited Aβ pathology, reduced NFT levels, and prevented astrocytic and microglial hyperactivity in the amygdala and hippocampus [132,160], showing that the anti-Aβ and anti-tau mechanisms of quercetin depend on its anti-inflammatory effects.Consequently, these mice demonstrated improved learning and memory and decreased anxiety [132], while combined exercise and quercetin treatment robustly improved spatial memory in AD rodents [161].Studies also found that quercetin enhanced cell viability and morphology by reducing MDA and ROS levels and increasing antioxidant SOD and GSH activity [159,162], limiting NF-κB signaling, restoring mitochondrial membrane potential to baseline, inhibiting tau hyperphosphorylation, and regulating Akt/PI3K/GSK-3β signaling pathway [159,163].Taken together, these data show that quercetin has a multimodal mechanism of action in treating AD.Of note, the anti-tau and consequent pro-neuroplastic effect of quercetin is further explored in Section 5, but the primary anti-inflammatory, anti-Aβ, ant-tau, and pro-neuroplastic effects of this flavonoid are all dependent on each other.

Kaempferol, Quercetin, and Neuroplasticity
The aberrant brain changes described in Section 3 can impair memory and cognitive function by creating deficits in neuroplasticity.Thus, future AD treatments should also be designed to directly target signaling pathways that can counteract the etiologies of AD.Specifically, we identified the PI3K/AKT signaling pathway as a critical candidate to counteract neurodegeneration.Several studies have suggested that flavonoids can alleviate learning and memory deficits by targeting this signaling pathway [29, [203][204][205].However, other pathways, including the MAPK-ERK1/2 cascade [206], have also been proposed and outlined in a recent review [207].In this section, we will first explore the impact of Aβand tau-mediated neuroinflammation on synaptic plasticity-related neuronal signaling.We will support the necessity of the PI3K/AKT/GSK-3β pathway in AD treatments and investigate the potential roles of kaempferol and quercetin in improving memory and cognition through this pathway.

Neuroplasticity Deficits in AD
An ideal AD treatment should enhance the expression of plasticity-related genes such as BDNF, a neurotrophic factor that regulates neuronal plasticity and survival [208][209][210][211][212][213][214].BDNF signaling begins with its binding to the receptor, Trkβ, activating signaling via a variety of pathways like PI3K/AKT [211,215].Then, AKT or protein kinase B (PKB) [216] can activate the CREB-mediated transcription of BDNF [217,218].Since Trkβ receptors mediate the pro-neuroplastic effects of BDNF [219], AD drugs must produce a direct or indirect effect on the receptor.

Kaempferol, Quercetin, and Neuroplasticity
The aberrant brain changes described in Section 3 can impair memory and cognitive function by creating deficits in neuroplasticity.Thus, future AD treatments should also be designed to directly target signaling pathways that can counteract the etiologies of AD.Specifically, we identified the PI3K/AKT signaling pathway as a critical candidate to counteract neurodegeneration.Several studies have suggested that flavonoids can alleviate learning and memory deficits by targeting this signaling pathway [29, [203][204][205].However, other pathways, including the MAPK-ERK1/2 cascade [206], have also been proposed and outlined in a recent review [207].In this section, we will first explore the impact of Aβand tau-mediated neuroinflammation on synaptic plasticity-related neuronal signaling.We will support the necessity of the PI3K/AKT/GSK-3β pathway in AD treatments and investigate the potential roles of kaempferol and quercetin in improving memory and cognition through this pathway.

Neuroplasticity Deficits in AD
An ideal AD treatment should enhance the expression of plasticity-related genes such as BDNF, a neurotrophic factor that regulates neuronal plasticity and survival [208][209][210][211][212][213][214].BDNF signaling begins with its binding to the receptor, Trkβ, activating signaling via a variety of pathways like PI3K/AKT [211,215].Then, AKT or protein kinase B (PKB) [216] can activate the CREB-mediated transcription of BDNF [217,218].Since Trkβ receptors mediate the pro-neuroplastic effects of BDNF [219], AD drugs must produce a direct or indirect effect on the receptor.
However, future AD treatments could reverse this toxic signaling via the following mechanism: A drug must either directly activate Trkβ or should do so indirectly by enhancing BDNF transcription [210].The drug can either directly activate PI3K and/or AKT, which would ultimately inhibit GSK-3β via the phosphorylation of its Ser9 residue [224].In turn, AKT can also inhibit caspase-9 and Bcl-3 to inhibit pro-apoptotic signaling [243][244][245][246].One study showed that the GSK-3β inhibitor, AR-A014418 (ARA), inhibited BACE1-mediated APP cleavage into Aβ proteins in rodents [48], supporting the necessity of a GSK-3βinhibiting drug for the treatment of AD.Finally, GSK-3β inhibition also reversed oxidative stress [93,247].In short, the PI3K/AKT pathway can not only reverse neuroinflammation but can also counteract Aβ-mediated tau hyperphosphorylation by inhibiting GSK-3β.

Quercetin and Kaempferol Resolve AD-Related Plasticity Deficits
The multimodal mechanisms of kaempferol and quercetin collectively slow neurodegeneration by combating the impairments that are illustrated in Figure 4A and are described in Table 1.Specifically, the restoration of proper PI3K/AKT signaling will greatly improve synaptic plasticity deficits in AD [7].While quercetin's interaction with each component of this signaling pathway has already been documented [7], kaempferol's mechanisms are still unclear.However, since kaempferol's structure is similar to that of quercetin [165], we propose that kaempferol has a nearly identical mechanism with respect to the signaling pathway in this subsection.Finally, we will propose the potential outcomes of these molecular interactions.
Table 1.Kaempferol and Quercetin and molecular interactions with select molecules relevant to neuroplasticity in AD.These affinity or potency values are deduced from molecular docking studies (affinity) and competition assays (IC50; potency) or were indirect interactions evidenced in the literature.Docking scores (DS) of 5 or higher indicate the high affinity of a compound for the protein of interest [248,249].Or, affinity from docking studies may be expressed as binding energies (BE) in -kcal/mol.The more negative the value, the higher the binding affinity.If studies have not supported direct binding to a certain target, the affinity column is noted as "Indirect".Molecular docking studies suggested that quercetin can bind PI3K, AKT, and GSK3β [213,250,[255][256][257]260,264,265].Specifically, quercetin can bind to PI3K [256], consequently activating AKT signaling [265], or quercetin can directly bind to AKT [257].In preclinical studies, quercetin reduced GSK-3β activity, which decreased tau hyperphosphorylation and reduced pro-apoptotic signaling [7,38,159].Quercetin treatment in rodents also increased BDNF, Trkβ, PI3K, and AKT expression [243,266].Consequently, quercetin enhanced neurite outgrowth in hippocampal neurons [36] and ameliorated the stress-induced downregulation of CREB and BDNF [40], suggesting that quercetin could potently replenish neuroplasticity in the AD brain.Moreover, quercetin inhibited Aβ by restoring Trkβ signaling and CREB-mediated BDNF transcription, increasing the viability of SH-SY5Y cells [252].Finally, quercetin's dual pro-neuroplastic and anti-inflammatory effects may also be related to the quercetin-mediated downregulation of BACE1 expression via the inhibition of NF-kB [253,254,264,267].Taken together, these data suggest that quercetin antagonizes Aβ-induced GSK-3β signaling relative to tau by activating the PI3K/AKT pathway and directly inhibiting GSK-3β [7,225,241,255,256,260]. Consequently, proper BDNF levels can be restored to replenish neuronal plasticity in the AD brain.Similar chemicals, such as epigallocatechin-3-gallate (EGCG), attenuated tau hyperphosphorylation in a similar mechanism [23,[268][269][270].Thus, quercetin clearly has dual neuroprotective and pro-neuroplastic mechanisms in cells [33,65,252], and the clinical outcomes of quercetin's pro-neuroplastic mechanisms were supported by its memory and cognition-boosting effects in rodent models of AD and Parkinson's disease [23,38,44,[271][272][273][274][275][276].Select molecular targets of quercetin are described in Table 1.
Despite the lack of literature demonstrating a direct modulation of tau by kaempferol, there is plenty of evidence to support the possibility that kaempferol inhibits tau hyperphosphorylation via the PI3K/AKT pathway and by antagonizing Aβ-mediated GSK-3β signaling [29, 149,195].This mechanism prevents neuronal degeneration and a loss of synaptic plasticity.Thus, the pro-neuroplastic effect of kaempferol requires the inhibition of GSK-3β and CREB phosphorylation.Remarkably, a recent molecular docking study suggested that kaempferol could bind to NMDAR [259].However, in vivo studies are still required to confirm this effect.
These data suggest a clear anti-AD mechanism of quercetin and kaempferol, as outlined in Figure 4B.First, quercetin and kaempferol could enter the cell cytoplasm due to their lipophilic polyphenolic structure.Quercetin and kaempferol scavenge ROS and activate PI3K/AKT signaling to inhibit GSK-3β.Specifically, they can bind directly to PI3K or AKT to activate protective signaling, inhibiting GSK-3β and preventing tau hyperphosphorylation.This signaling cascade reduces the formation of NFTs in the AD brain.GSK-3β inhibition can also antagonize Aβ-NMDAR interactions.Thus, downstream pro-apoptotic signaling mediators are also inhibited by quercetin and kaempferol treatment.Due to reduced NFT and amyloid plaque formation, microglial hyperactivity decreases in the absence of the burden of clearance.Thus, progressive neuroinflammatory signaling is slowed, allowing surrounding neuronal synapses to survive.After chronic quercetin treatment, progressive elevations in BDNF release rebuild damaged synapses by favoring neurotrophic signaling over cytotoxic Aβ signaling, improving memory and cognition.Of note, molecular docking studies have not supported the possibility that kaempferol and quercetin can directly bind to tau protein, supporting their indirect inhibitory mechanism via GSK-3β inhibition.Taken together, kaempferol and quercetin share multiple mechanisms that slow AD progression by first limiting ROS activity, NFT aggregation, and Aβ-mediated toxic signaling, slowing neurodegeneration.

Quercetin and Kaempferol in Common Herbs
Although data on the co-treatment of quercetin and kaempferol are still somewhat limited, the abundance of both compounds in several common herbs requires the investigation of the synergistic effects of both flavonoids, in addition to their interactions with other herbal phytochemicals.Flavonoid-rich herbs are commonly employed in traditional Chinese medicine (TCM), in which an emphasis is placed on the utility of natural treatments.Moreover, these herbs are generally safe for consumption [224].Kaempferol is the second most common flavonoid in traditional medicinal herbs, following quercetin [225,284].Other reviews have assessed the efficacy and safety of natural medicine in the treatment of neurodegenerative diseases [7,224], highlighting the potential medicinal

Quercetin and Kaempferol in Common Herbs
Although data on the co-treatment of quercetin and kaempferol are still somewhat limited, the abundance of both compounds in several common herbs requires the investigation of the synergistic effects of both flavonoids, in addition to their interactions with other herbal phytochemicals.Flavonoid-rich herbs are commonly employed in traditional Chinese medicine (TCM), in which an emphasis is placed on the utility of natural treatments.Moreover, these herbs are generally safe for consumption [224].Kaempferol is the second most common flavonoid in traditional medicinal herbs, following quercetin [225,284].Other reviews have assessed the efficacy and safety of natural medicine in the treatment of neurodegenerative diseases [7,224], highlighting the potential medicinal properties of herbs in treating AD.Flavonoids are commonly found in herbs such as Schima wallichii Korth, Maesa membranacea, Ginkgo biloba, and many more [175,225,278].These phytochemicals could work synergistically with each other and with other herbal components to invoke anti-AD effects.Thus, we explore common herbal sources of kaempferol and quercetin, describe the anti-AD mechanisms of herbs, and propose a design for a future AD treatment based on the current evidence of these effects.
Polyherbal cocktails, such as Chaihu shugan san (CSS) and Huangqi Sijunzi (HQSJDZ), could treat AD and its risk factors.CSS is abundant in kaempferol and quercetin and contains herbs such as Glycyrrhiza uralensis, Cyperus rotundus, and Buplerum falcatum [256].Specifically, the antidepressant effect of CSS is mediated by increased PI3K/AKT/BDNF signaling and decreased GSK-3β and IL-2 activity [256], suggesting that polyherbal cocktails may be protected from AD development.HQSJDZ, rich in kaempferol and quercetin, had cholinergic, anti-inflammatory, and anti-GSK-3β effects [278,306].Moreover, a cocktail of C. sinensis, Hypericum perforatum, and Bacopa monnieri produced robust antioxidant effects compared to single-herb treatment [298].These data suggest that polyherbal treatment may be superior to single-herb therapy.
Due to the well-documented effects of quercetin and kaempferol on Aβ, GSK-3β, PI3K/AKT, and multiple pro-inflammatory molecules, it is possible that both phytochemicals, given their abundance, contribute vastly to the anti-AD effects of several herbs.Such herbs include Ginkgo biloba, Camellia sinensis, Glycyrrhiza uralensis, Cyperus rotundus, and Buplerum falcatum.The herbal sources outlined in Table 2 may also be great additions to the treatment protocol that can enhance the dietary intake of kaempferol and quercetin.According to the practice of TCM, it is possible that a multi-herb cocktail containing varying amounts of these herbs could alleviate AD symptoms, as seen with current medications, but it may also halt progression relative to a unique multi-modal mechanism.Multiple studies have suggested that the synergistic effects of polyherbal treatments produce greater anti-AD efficacy compared to single-herb treatment [256,278,298].Thus, the research and development of future AD drugs should consider the applications of these common herbs in future drug cocktails.On the other hand, since clinical trials featuring Ginkgo biloba extracts have demonstrated controversial results on the progression of AD [296], single-herb treatments may be insufficient to treat AD.
Despite its lipophilicity and easy oral administration in common foods, quercetin treatment for AD may be challenged by its limited bioavailability relative to the brain [3,258].Since quercetin absorption is predominantly mediated by the small intestine, it is vulnerable to extensive first-pass metabolism [133,258,325].While its distribution was evidenced in the plasma, liver, heart, spleen, kidneys, and lungs, quercetin levels were non-detectable in the rat brain [326,327].Hence, it has around 65% BBB permeability [321,328] and is absorbed in the stomach with 24-53% bioavailability [329].The P-glycoprotein transporter, which is a BBB efflux transporter, has a high affinity for free, unaltered quercetin and greatly reduces its bioavailability by pumping quercetin away from the brain [51,330].While in vitro studies showed the promising antioxidant effects of quercetin, most studies in animal models have demonstrated limited efficacy [3,331].These data show that quercetin's limited bioavailability could debilitate anti-AD effects [258].
Chemical modifications are necessary to ensure quercetin distribution to the brain, as some metabolites may also have higher efficacy than quercetin alone.For instance, quercetin-glucoside conjugation enhanced its bioavailability [129].Quercetin glycosides are commonly available in fruits and vegetables, improving its delivery to the CNS [51,332].Glucuronidation in the liver also increased the distribution of quercetin to the brain in oxidative stress models [23].Moreover, in vivo studies showed that lipid nanoparticleloaded quercetin enhances its entry into the brain [39,44,146,158,163,333,334].Moreover, quercetin loading into selenium nanoparticles improved brain distribution and anti-Aβ mechanisms [335].However, excess selenium levels in the body can produce oxidative stress [336,337], potentially limiting the clinical efficacy of this approach.
Like quercetin, free kaempferol generally has low oral bioavailability due to metabolic degradation [324,338,339].Kaempferol is generally slowly absorbed in the GI tract and can be distributed to several tissues [326,340], suggesting that the primary limitation of kaempferol treatment is limited bioavailability.However, several modifications to improve its BBB permeability have been proposed.First, nanoparticle loading also improves kaempferol bioavailability [194,334,[341][342][343][344], and kaempferol-sugar conjugates also demonstrate superior protective efficacy [36].For instance, nanoparticle-loaded kaempferol has more robust anti-inflammatory effects than kaempferol alone [68].Clinical trials revealed that quercetin had superior memory-modulating activity in AD patients compared to healthy elderly controls [345][346][347], suggesting that the increased BBB permeability in AD may, in turn, improve flavonoid bioavailability and efficacy in neurodegenerative brains.Several other forms of delivery have been proposed for both flavonoids, including gold-infused nanoparticles [348,349], multi-targeted drugs [350], extracellular vesicles [351], and intranasal administration [352].Finally, other proposed nanoformulation delivery systems include nanomatrixes, nanoemulsions, nanostructured lipid carriers, and nanocomplexes [343,344,353].

Adverse Health Effects and Other Limitations
Most studies show promising medical benefits for kaempferol and quercetin and suggest that they are safe in a variety of doses.For example, quercetin is included in the Food and Drug Administration's Generally Recognized as Safe (GRAS) list for supplemental use of up to 500 mg per serving in foods and beverages [129,354].However, flavonoids' clinical efficacy may also be limited by adverse effects [329].While the Ames test suggested that quercetin could have carcinogenic properties, most studies have opposed this finding and suggested that quercetin is safe [355].One study suggested that high-dose quercetin treatment reduced neuronal survival, induced oxidative stress, and inhibited AKT [356].Thus, physicians should carefully manage the abundance of quercetin in the AD patient's diet to maintain its proper anti-degenerative effects.Moreover, the efficacy of quercetin may be limited in AD patients who are also diagnosed with leukemia, as quercetin inhibits the PI3K/AKT signaling pathway in HG3 cells [282].It is possible that, since most dietary quercetin is distributed to peripheral sites, lower concentrations in the brain may decrease its efficacy in AD.
Although kaempferol is most likely safe to consume [339] and most studies showed low toxicity in mice [357][358][359], some studies have reported concerns about potential mutagenic effects in people with iron and folic acid deficiencies [338,339,360].Since the excess inhibition of GSK-3β may produce toxic effects in cells [233], kaempferol's low-affinity GSK-3β interactions may underlie its generally low toxicity.In a 4-week randomized, double-blind clinical trial, participants were divided into a group that received 50 mg of kaempferol daily and a placebo group; kaempferol was reported as mostly safe, but the small sample size of 24 in each group limits this study [359].Overall, the majority of work on the herb suggests it to be safe, even in high doses, but more clinical trials are highly recommended.

Discussion
Since AD still lacks a true cure, and currently available medications are insufficient to halt disease progression, the field has sought out multimodal treatments for AD.However, little progress in drug development has been made in recent decades, necessitating new alternative treatments.Thus, the objective of this review was to deduce the anti-AD mechanisms of kaempferol and quercetin.These phytochemicals were selected for multiple reasons, including their abundance [38,116] and their multimodal mechanisms (Figure 5) that include antioxidant, anti-inflammatory, pro-neuroplastic, and neuroprotective effects.Thus, quercetin and kaempferol may treat Alzheimer's disease, and we aimed to explore their anti-amyloidogenic, antioxidant, anti-inflammatory, anti-tau, and pro-neuroplastic mechanisms [6,29,38,39,51,127,128,149,159,167,361].In turn, phytochemicals may not only reduce AD symptoms [29, 33,132] but also delay the progression of the disorder.Of note, the efficacy of these flavonoids to produce the effects outlined in this review depends on any chemical modifications that may occur throughout the absorption and distribution of phytochemicals to the brain.
Perhaps the most significant contribution of this review is the complex anti-degenerative mechanism of kaempferol.We utilized the available literature to show that kaempferol's dual anti-tau and anti-Aβ mechanisms are due to its modulation of the PI3K/AKT/GSK-3β signaling pathway.Both phytochemicals resolve oxidative stress by increasing antioxidant levels and inhibiting ROS signaling [119].Meanwhile, they halt inflammatory signaling [29,38] to commence a neuroprotective effect.Then, resolved microglial and astrocytic activity facilitates proper Aβ clearance from the brain [6] and reduces continued neuronal damage due to the neuroinflammatory environment [122,188,195].The modulation of PI3K/AKT/GSK-3β and Trkβ/BDNF signaling potentiates neuroplasticity and protects neurons from insults like Aβ [10,240], decreasing tau hyperphosphorylation and preserving the neuronal cytoskeletal structure.These phytochemicals, in turn, protect neuronal networks [33,40], improving memory and cognitive function in AD patients.Other flavonoids with heterocyclic structures [362], including morin [363-366], rutin [367,368], and luteolin [369][370][371], share many similar anti-AD properties relative to kaempferol and quercetin.However, rutin [368] failed to increase BDNF levels, like kaempferol and quercetin.
Due to the superior efficacy of polyherbal treatments, such as HQSJDZ and CSS [256,278,298], we proposed that polyherbal treatment, containing quercetin-and kaempferol-rich herbs like Ginkgo biloba, Camellia sinensis, Glycyrrhiza uralensis, Cyperus rotundus, and Buplerum falcatum may produce superior anti-AD efficacy compared to singleherb supplements.Recent studies also suggested that herbs such as Morenga oleifera, Cuscuta chinensis, Allium cepa, Hippophae rhamnoides, Litchi chinensis, Prakia roxburghii, Radix astragali, Fagopyrum tataricum, and Carthami flos [251,294,[301][302][303][304] may also be candidates for polyherbal treatment.However, a recent review noted that kaempferol and quercetin are widely available in hundreds of herbs, and it is possible that they may not be as abundant as other phytochemicals in some species [372], supporting the necessity of polyherbal treatment to obtain biologically effective concentrations.

Conclusions
Kaempferol and quercetin clearly exhibit multimodal mechanisms that halt AD progression and alleviate symptoms.Given the multifaceted nature of AD pathogenesis, future treatments need to adopt a multimodal approach that targets the Aβ-tau signaling pathway via the modulation of the PI3K/AKT/GSK3β signaling cascade, leading to a proneuroplastic effect via enhanced BDNF signaling.To our knowledge, our review demonstrates how kaempferol and quercetin address various aspects of AD, including neuroinflammation, oxidative stress, reduced plasticity, and Aβ and tau signaling.Notably, our review is the first to propose that kaempferol can mitigate both tau hyperphosphorylation and Aβ toxicity by directly targeting the PI3K/AKT/GSK3β pathway.Additionally, we suggest that polyherbal cocktails rich in kaempferol and quercetin may yield robust anti-AD effects, and we identified potential herbal sources of kaempferol and quercetin.Finally, we discuss the limitations that currently impede the efficacy of kaempferol/quercetin treatment, and suggest potential adjustments to circumvent these challenges.Together, As previously mentioned, clinical trials suggest that kaempferol and quercetin could treat AD in humans [135,346,347,373,374], but single-herb treatment was unsuccessful in clinical trials [296].Future trials should assess bioavailability-enhancing delivery methods for quercetin and kaempferol.However, recent studies also suggested that both quercetin and kaempferol have the ability to maintain and protect BBB integrity [375][376][377][378][379].This could possibly be due to their anti-inflammatory properties that could be invoked if they reach the brain.Of course, clinical trials should continue to assess the efficacy of herbal sources in AD-related symptoms.However, the misuse of herbal treatments may produce side effects, including gastrointestinal discomfort, insomnia, and tachycardia [298].Thus, studies assessing these side effects are limited and require further investigation [36,37].Nonetheless, these natural herbs are generally considered safe, and toxic effects are uncommon [51,116,142].Finally, an investigation of interactions between these polyphenols and other drugs commonly prescribed to AD patients is required.
Although the data presented in this review showcase the great potential of these herbs in AD treatment, a few limitations have impacted this review.Specifically, studies investigating the tau hyperphosphorylation-inhibiting mechanisms of these herbs may be limited due to the rapid dephosphorylation of the protein in postmortem AD tissues [15,279].Moreover, the abundantly described bioavailability limitations of both herbs critically limit the efficiency of human studies.This could be one reason underlying the lack of kaempferol and quercetin's clinical efficacy to date.Clinical trials investigating compounds that increase the bioavailability of these phytochemicals are still needed.Since quercetin and kaempferol are naturally abundant in the average diet, future clinical trials can be easily conducted.Finally, while molecular docking studies show the potential pharmacodynamic interactions between kaempferol/quercetin and the outlined pro-neuroplastic targets, these approaches are merely estimates of binding affinity based on the crystal structures of the target protein and the molecular structures of the ligand, and they could be vulnerable to mispredictions [380].Thus, future studies must either employ competition assays or ligand inhibitor/antagonist studies to confidently elucidate the true affinity of kaempferol and quercetin for the targets of interest.Nonetheless, recent data support the exciting potential of kaempferol and quercetin to slow the progression of AD and alleviate the symptoms.

Conclusions
Kaempferol and quercetin clearly exhibit multimodal mechanisms that halt AD progression and alleviate symptoms.Given the multifaceted nature of AD pathogenesis, future treatments need to adopt a multimodal approach that targets the Aβ-tau signaling pathway via the modulation of the PI3K/AKT/GSK3β signaling cascade, leading to a pro-neuroplastic effect via enhanced BDNF signaling.To our knowledge, our review demonstrates how kaempferol and quercetin address various aspects of AD, including neuroinflammation, oxidative stress, reduced plasticity, and Aβ and tau signaling.Notably, our review is the first to propose that kaempferol can mitigate both tau hyperphosphorylation and Aβ toxicity by directly targeting the PI3K/AKT/GSK3β pathway.Additionally, we suggest that polyherbal cocktails rich in kaempferol and quercetin may yield robust anti-AD effects, and we identified potential herbal sources of kaempferol and quercetin.Finally, we discuss the limitations that currently impede the efficacy of kaempferol/quercetin treatment, and suggest potential adjustments to circumvent these challenges.Together, these changes can improve the anti-AD efficacy of natural flavonoids and could be ideal adjunctive or alternative treatments to currently available drugs.

Figure 1 .
Figure 1.Flowchart depicting the article screening and selection process according to PRISMA guidelines.

Figure 1 .
Figure 1.Flowchart depicting the article screening and selection process according to PRISMA guidelines.

Figure 4 .
Figure 4. (A) Neuroplasticity deficits accelerate AD progression and must be treated.Impaired PI3K-AKT signaling facilitates GSK3β-mediated phosphorylation of tau.Aβ may potentiate tau hyperphosphorylation via GSK3β.(B) Kaempferol and quercetin (K/Q) invoke the PI3K/AKT pathway to antagonize Aβ and reduce tau hyperphosphorylation in neurons.As a result, neuroplasticity is increased in the AD brain [283].

Biology 2023 , 33 Figure 5 .
Figure 5.A graphical summary of the underlying mechanisms behind AD progression (pathogenesis), the proposed mechanisms of kaempferol and quercetin (K/Q), where K/Q represents kaempferol and quercetin, and the impact of these molecular changes on behavior and disease progression (outcomes).Each category is presented in a top-tobottom chronological order.

Figure 5 .
Figure5.A graphical summary of the underlying mechanisms behind AD progression (pathogenesis), the proposed mechanisms of kaempferol and quercetin (K/Q), where K/Q represents kaempferol and quercetin, and the impact of these molecular changes on behavior and disease progression (outcomes).Each category is presented in a top-to-bottom chronological order.

Table 2 .
Plant sources of kaempferol and quercetin and/or their metabolites and a description of reported herbal health effects.