Natural Products Targeting Tau Protein Phosphorylation: A Promising Therapeutic Avenue for Alzheimerʼs Disease

Abstract

Alzheimerʼs disease is a progressive neurodegenerative disorder characterized by tau protein hyperphosphorylation and neurofibrillary tangle formation, which are central to its pathogenesis. This review focuses on the therapeutic potential of natural products in targeting tau phosphorylation, a key factor in Alzheimerʼs disease progression. It comprehensively summarizes current research on various natural compounds, including flavonoids, alkaloids, saponins, polysaccharides, phenols, phenylpropanoids, and terpenoids, highlighting their multitarget mechanisms, such as modulating kinases and phosphatases. The ability of these compounds to mitigate oxidative stress, inflammation, and tau pathology while enhancing cognitive function underscores their value as potential anti-Alzheimerʼs disease therapeutics. By integrating recent advances in extraction methods, pharmacological studies, and artificial intelligence-driven screening technologies, this review provides a valuable reference for future research and development of natural product-based interventions for Alzheimerʼs disease.

Keywords

Alzheimerʼs disease - tau phosphorylation - natural products - glycogen synthase kinase 3β (GSK-3β) - protein phosphatase 2A (PP2A) - neuroprotection

Introduction

Alzheimerʼs disease (AD) is a prevalent neurodegenerative disorder predominantly affecting individuals aged 65 and older. Clinically, it is characterized by progressive memory decline and cognitive impairment. With the aging population and increasing life expectancy, the prevalence of dementia among the elderly is rising, making AD the most common form of dementia, accounting for approximately 70% of all cases. It has become a major cause of mortality, following cardiovascular diseases, cerebrovascular diseases, and cancer, posing a severe threat to the physical and mental health of the elderly [1].

Despite extensive research, the pathogenesis of AD remains unclear. Emerging evidence suggests its association with several factors, including amyloid-beta (Aβ) deposition, abnormal tau protein phosphorylation, neuroinflammation, neuronal apoptosis, and oxidative stress [2]. The Aβ hypothesis has been widely acknowledged and remains a focal point in AD research. Accordingly, numerous therapeutic strategies have been developed, aiming to clear Aβ plaques, inhibit Aβ aggregation and deposition, or reduce Aβ production in the brain by targeting γ-secretase and β-secretase. However, these approaches require further validation in clinical trials [3], [4], [5]. The development of novel therapeutics targeting potential targets in AD has been a major focus of research in recent years. However, many of these candidates have encountered significant setbacks during phase II and III clinical trials, highlighting the challenges of developing effective treatments for AD. Bapineuzumab, an anti-Aβ monoclonal antibody, failed to demonstrate significant improvements in cognitive function and activities of daily living in patients with mild to moderate AD across two phase III clinical trials, resulting in the termination of its development [6]. Similarly, semagacestat, a γ-secretase inhibitor, not only failed to enhance cognition and function in phase III trials but also induced severe adverse effects, including an increased risk of skin cancer and infections, leading to its discontinuation [7].

Verubecestat, a beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor developed for the treatment of early-stage AD, also failed to show significant improvements in cognitive function in phase II/III trials and presented safety and tolerability concerns, contributing to its development failure [8]. AN1792, an Aβ immunotherapy designed to stimulate an immune response by injecting Aβ peptides to clear Aβ deposits in the brain, had to halt its phase II trial due to the occurrence of severe side effects, such as meningoencephalitis, in some patients, resulting in the discontinuation of its development [9]. These examples underscore the substantial challenges in developing novel therapeutics targeting various pathways in AD pathogenesis, despite the extensive research efforts and resources invested in this field.

Currently, there is an urgent need for effective interventions for AD, necessitating the exploration of novel therapeutic agents. Increasing attention is being directed toward the tau protein pathology hypothesis, with drug development focusing on tau protein phosphorylation gaining momentum [10]. Abnormal tau phosphorylation is influenced by various pathological factors, including dysregulated kinase activity, aberrant gene expression, chronic stress, and disease conditions, leading to excessive aggregation and the formation of neurofibrillary tangles (NFTs) [11], [12], [13]. NFTs contribute to synaptic loss, axonal transport dysfunction, mitochondrial and cytoskeletal impairments, and oxidative stress. These pathological changes play a critical role in the development of tau-related neurodegenerative disorders. Studies indicate that modulating tau phosphorylation processes could be a promising approach for preventing and treating AD [14].

For decades, researchers have consistently explored natural products as a valuable source of therapeutic compounds, recognizing their critical role in drug discovery and development [15]. Natural products are rich in diverse bioactive components, characterized by their unique ability to exert multicomponent, multitarget effects. This feature offers significant potential advantages for addressing the multifactorial and complex pathological mechanisms of AD. With advancements in modern extraction and separation technologies, the identification of highly effective, low-toxicity, and stable anti-AD active ingredients from natural products has become a promising strategy for the development of anti-AD therapeutics.

This review categorizes these compounds and based on the tau protein pathology hypothesis in the progression of AD, examines the mechanisms through which anti-AD active ingredients derived from natural products interfere with tau protein phosphorylation. The goal is to provide a robust scientific basis to support the further development of innovative anti-AD drugs.

Materials and Methods

A systematic literature review was conducted to investigate the effects of natural products on tau hyperphosphorylation in AD. The review process involved searching authoritative databases including PubMed/MEDLINE, Web of Science Core Collection, Scopus, and the Natural Products Alert (NAPRALERT) Database. The search strategy utilized a combination of primary terms (“natural products” OR “phytochemicals” OR “botanical compounds”, “tau protein” OR “tau phosphorylation” OR “tau hyperphosphorylation”, “Alzheimerʼs disease” OR “neurodegeneration”) and secondary terms (“traditional medicine” OR “medicinal plants”, “kinase inhibitors” OR “phosphatase activators”, “neuroprotection” OR “cognitive function”) linked with Boolean operators. The literature search spanned publications from January 2003 to December 2024, with emphasis on studies from the last decade (2014 – 2024) to ensure currency. Inclusion criteria were original research articles, systematic reviews, meta-analyses, peer-reviewed publications, studies with clear methodology and reproducible results, and both in vitro and in vivo studies. The primary focus was on English-language publications to ensure accessibility and peer review.

Tau protein is involved in the pathogenesis of Alzheimerʼs disease

The abnormal phosphorylation of tau protein is widely recognized as a hallmark of AD, closely associated with the formation of NFTs characteristic of the disease. Tau protein, a microtubule-associated protein, is essential for promoting microtubule assembly, stabilizing their structure, and maintaining axonal transport. It plays a pivotal role in organizing the neuronal cytoskeleton, with its activity predominantly regulated by its phosphorylation status. Under physiological conditions, moderate phosphorylation of tau is necessary to maintain its normal functions. However, the imbalance between kinase and phosphatase activity that leads to tau protein hyperphosphorylation can drive tau to reach a pathological threshold. This causes its dissociation from microtubules, triggering a cascade of reactions that ultimately contribute to the progression of AD ([Fig. 1]). Additionally, tau protein influences both the plasma membrane and microtubule dynamics within neuronal cells. It is present in synapses and dendrites, where it supports neuronal maturation and modulates synaptic function. Disruptions in the synaptic distribution of tau and its interactions with synaptic proteins can impair neuronal function, contributing to the pathogenesis of AD [13].

Fig. 1 The process of abnormal phosphorylation of tau in AD.

The abnormal phosphorylation and aggregation of tau protein, culminating in the formation of NFTs, is a critical process in the pathogenesis of AD. This mechanism is regulated by various kinases and phosphatases. Phosphorylation sites on tau protein, including threonine (Thr), serine (Ser), and tyrosine (Tyr) residues, are modified under the influence of kinases, resulting in a phosphorylated tau protein [16]. Phosphorylated tau dissociates from microtubules, destabilizing them and leading to cytoskeletal collapse. The dissociated phosphorylated tau adopts a double helix structure, aggregates into NFTs, and contributes to AD progression.

Tau kinases, particularly glycogen synthase kinase 3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), are pivotal in this process. Abnormal kinase expression is a primary driver of tau hyperphosphorylation. Among these, GSK-3β is the most extensively studied. Its upregulation promotes tau hyperphosphorylation through pathways such as PI3K/AKT/GSK-3β. Phosphatidylinositol 3,4,5-triphosphate (PIP3), a key secondary messenger in the phosphoinositide 3-kinase (PI3K) pathway, elevates PI3K activity, leading to excessive protein kinase B (AKT) activation. This process significantly phosphorylates GSK-3β, contributing to tau hyperphosphorylation in AD [17], [18]. CDK5, unlike other cyclin-dependent kinases, functions predominantly in neurons. Its overexpression results in tau hyperphosphorylation and the formation of paired helical filaments (PHFs), regulated by activator proteins p35 and p39 [18]. Under neuronal damage and exposure to toxic factors such as oxidative stress, glutamate, ischemic injury, mitochondrial dysfunction, Aβ, and inflammation, elevated calcium influx activates calpain, which cleaves p35 and p39 into more stable CDK5-p25 and CDK5-p29 complexes. These complexes exhibit heightened activity, exacerbating tau phosphorylation. In vitro studies indicate that p39 is more effective than p35 in activating CDK5 for tau phosphorylation, leading to overactivation of CDK5 and excessive tau phosphorylation [19], [20]. Additionally, other kinases, including microtubule affinity-regulating kinase (MARK), mitogen-activated protein kinase (MAPK), protein kinase II, protein kinase A (PKA), protein kinase C (PKC), c-Jun N-terminal kinase (JNK), death-associated protein kinase 1 (DAPK1), and Ca2+/calmodulin-dependent protein kinase II (CaMKII), are also implicated in tau phosphorylation [21], [22], [23], [24], [25], [26], [27], [28].

Conversely, phosphatases play a critical role in removing phosphate groups from phosphorylated tau protein, thereby restoring its physiological functionality. Protein phosphatase 2A (PP2A), a Ser/Thr phosphatase, is composed of three subunits: the structural A subunit, the catalytic C subunit, and the regulatory B subunit. In AD, the C subunit forms the core enzyme, with its methylation status regulating PP2A activity [29]. Studies have shown that inhibition of PP2A, mediated by the activation of the lysosomal enzyme asparagine endopeptidase (AEP) and the cleavage of I₂ ^PP2A, contributes to the excessive phosphorylation of tau and the proliferation of NFTs [30]. Elevated AEP levels in the brain cleave I₂ ^PP2A into I_2NTF and I_2CTF fragments, ultimately inhibiting PP2A and leading to tau hyperphosphorylation [31]. Additionally, the B subunit PPP2R2A of PP2A has been found to regulate tau dephosphorylation directly or indirectly via the GSK-3β pathway [32]. Mass spectrometry analysis of B subunit-specific phosphorylation sites in tau has revealed that PP2A may influence the phosphorylation state of tau, depending on the specific B subunit. One key regulatory subunit of PP2A is the PP2A phosphatase activator protein (PTPA), also known as regulatory subunit 4 (PPP2R4). PTPA exhibits isomerase activity and ATP-binding capability, suggesting that PP2A regulation is intricately linked to conformational changes in the phosphatase [33].

From numerous studies, it is evident that kinases and phosphatases interact intricately, collectively influencing tau protein phosphorylation through various mechanisms. CDK5 primarily regulates GSK-3β activation via two key pathways. Specifically, CDK5 inhibits protein phosphatase 1 by activating its inhibitors, leading to increased phosphorylation of GSK-3β at specific sites, including Ser199, Ser202, Thr231, Ser396, Ser400, and Ser412 [34]. Additionally, CDK5 can activate epidermal growth factor (ErbB) receptors, thereby stimulating AKT and interacting with GSK-3β through phosphorylation [35]. Notably, the GSK-3β and PP2A pathways exhibit a collaborative relationship. Studies indicate that overexpression of GSK-3β can induce PP2Ac methylation through protein phosphatase methylesterase-1 (PME-1) and leucine carboxyl methyltransferase 1 (LCMT1). Conversely, inhibition of PP2A enhances Ser9 phosphorylation of GSK-3β, thereby reducing its activity [36]. The dysregulation of these kinases and phosphatases results in abnormal tau phosphorylation, either directly or through their interactions.

The phosphorylation level of tau protein is also influenced by related signaling pathways, particularly the intracellular PI3K/AKT/GSK-3β pathway, which plays a central role in cell growth, survival, apoptosis, and proliferation. Dysregulation of this pathway can lead to tau hyperphosphorylation, contributing to the pathology of AD. Furthermore, tau protein lesions and Aβ deposition are closely linked as hallmark features of AD. The abnormal accumulation and aggregation of Aβ in the brain induce neurotoxicity, serving as a primary event in AD progression. Aβ further exacerbates tau pathology, leading to its hyperphosphorylation and accelerating disease progression [37]. Aβ interacts with MARK, promoting tau aggregation and advancing AD onset and progression [21]. Thus, targeting tau hyperphosphorylation is of critical importance in mitigating Aβ deposition and slowing the progression of AD.

Therapeutic strategies targeting tau kinase/phosphatase

Currently, many therapeutic strategies for AD yield limited efficacy and fail to prevent or reverse disease progression. Numerous phase II or III clinical trials targeting Aβ accumulation in the brain have ended unsuccessfully, shifting researchersʼ focus to tau pathology. Approaches targeting tau include inhibition of tau kinases/phosphatases, active and passive immunization, and strategies to prevent tau protein aggregation [38].

The mechanisms underlying tau hyperphosphorylation, particularly those involving tau-related kinases such as GSK-3β and CDK5, have been previously discussed. Studies suggest that treating tau transgenic mice with the nonspecific protein kinase inhibitor K252a (targeting CDK5, GSK-3β, and ERK1) can reduce the soluble aggregated hyperphosphorylated tau protein and improve motor symptoms [39]. Given the central role of GSK-3β in tau pathology, suppressing GSK-3β expression remains a critical therapeutic goal. Unfortunately, short-term inhibitors like lithium chloride and tideglusib (NP-12) have failed to meet expectations. Moreover, the lack of robust data on long-term kinase inhibitors underscores the need for further investigations. Several compounds, including Ara0114418, AZ10316813, AZ11125357, CHIR98014, SB216763, SB415286, SRN-003 – 556, and valproate, have shown efficacy in inhibiting GSK-3β and reducing tau levels [40]. Among these, thiadiazolidinones (TDZDs) represent the first selective GSK-3β inhibitors to enter phase I clinical trials [41]. Cerebrolysin has demonstrated the ability to reduce p-tau levels, lower Drp-1 levels, and normalize mitochondrial morphology by modulating the GSK-3β and CDK5 pathways [42]. Furthermore, inhibition of 12/15-lipoxygenase (12/15LO) has emerged as a potential molecular target for AD treatment, as 12/15LO independently regulates tau phosphorylation through CDK5 and stress-activated SAPK/JNK pathways [43]. However, these kinases have numerous substrates beyond tau protein, raising concerns about the safety and specificity of kinase inhibitors [44]. To date, no tau kinase inhibitor has successfully progressed to late-stage clinical trials for AD.

Another promising approach involves enhancing the activity of protein phosphatases to facilitate the removal of phosphate groups from tau protein. In AD patients, reduced levels of folate and methylfolate lead to elevated homocysteine levels, which promote the methylation of PP2Ac. This methylation process forms the active PP2A complex containing the Bα subunit, thereby enhancing tau dephosphorylation [39]. Memantine, a drug capable of increasing PP2A activity, has been administered to AD patients for up to 1 year. It effectively crosses the blood-brain barrier and significantly reduces phosphorylated tau levels in cerebrospinal fluid. With an oral administration route, memantine exhibits an absolute bioavailability of approximately 100% [45]. Additionally, dietary supplementation with the PP2A methylesterase inhibitor eicosanoyl-5-hydroxytryptamine has been shown to reduce tau hyperphosphorylation in AD rat models [31]. Similarly, long-term administration of low-dose metformin and sodium selenate has demonstrated the potential to enhance PP2A activity by stabilizing protein phosphatase. Metformin, an orally administered drug, has a bioavailability ranging from 50 – 60%; however, its ability to cross the blood-brain barrier remains under investigation [39]. Despite the promise of enhancing PP2A activity to inhibit tau hyperphosphorylation, it is critical to consider that PP2A participates in multiple signaling pathways essential for maintaining normal cellular homeostasis. Thus, strategies to augment PP2A activity must be carefully optimized to minimize potential side effects.

Natural active ingredients targeting tau protein phosphorylation intervene in Alzheimerʼs disease

Natural products have been extensively utilized in disease treatment and have demonstrated efficacy in both traditional and modern medicine. In 2023, natural drugs accounted for 34.5% of all FDA-approved pharmaceuticals [46]. Traditional Chinese medicinal herbs represent a rich source of natural medicines. Modern pharmacological studies reveal that natural remedies such as Polygonum multiflorum [47], Epimedium [48], and Cuscuta [49], known for their roles in nourishing the liver and kidneys, can alleviate kidney yang deficiency syndrome, enhance spatial learning and memory, and reduce tau protein hyperphosphorylation. These effects are mediated through the inhibition of GSK-3β activity and modulation of the PI3K/AKT/GSK-3β signaling pathway. Ginseng, another well-studied natural product, has been shown to upregulate the activity of protein phosphatase PP2A, inhibit ERK1/2 kinase, and reverse tau protein hyperphosphorylation, thus demonstrating therapeutic potential in AD treatment [50]. Similarly, herbs such as Bupleurum chinense, Angelica sinensis, and Paeonia lactiflora exhibit cognitive-enhancing effects through distinct mechanisms. These effects are primarily associated with the regulation of cholinergic nerves, along with neuroprotective actions mediated by anti-inflammatory and antioxidant properties. Additionally, these herbs target key components of the IRS1/GSK-3β/Wnt3a-β-catenin pathway, effectively inhibiting tau protein hyperphosphorylation [51]. Phlegm turbidity and heat toxins, including pathological products such as Aβ, free radicals, and inflammatory factors, are considered harmful byproducts in the human body. According to the theory of “toxic damage to brain collaterals”, Coptis chinensis is widely applied in modern clinical practice. Experimental studies have demonstrated that it can downregulate the NLRP3 inflammasome signaling pathway, inhibit microglial activation, and reduce levels of toxic pathological products such as Aβ and p-tau, thereby alleviating neuronal damage [52]. Additionally, research suggests that gastrointestinal dysbiosis interferes with neural signaling in the brain through endocrine and other pathways, contributing to brain diseases. Danggui Shaoyao powder and Huanglian Jiedu decoction have been shown to influence the development of dementia by modulating the composition and distribution of gut microbiota [53], [54]. Other studies indicate that Alpinia oxyphylla and Schisandra chinensis regulate the PI3K/AKT/GSK-3β/CREB pathway, effectively suppressing tau protein overexpression [55]. Furthermore, Acorus tatarinowii and Polygala tenuifolia have been reported to reduce Aβ production, regulate tau protein hyperphosphorylation, inhibit acetylcholinesterase (AchE) activity, balance neurotransmitter levels, decrease inflammatory factor production, mitigate oxidative stress, enhance neuronal synaptic plasticity, and provide neuroprotective effects in AD [56]. In conclusion, numerous natural drugs can delay the progression of AD by modulating tau protein phosphorylation, offering promising therapeutic potential.

Natural products are secondary metabolites with distinct biological activities, extracted and isolated from plants, animals, microorganisms, and marine organisms. These molecules, characterized by specific structures and bioactivities, serve as vital resources for drug development. The initial stage in the isolation and purification of natural products involves the extraction of components to obtain crude extracts containing the target compounds from natural medicines. Solvent extraction remains the most widely employed traditional extraction method, with the diffusion and solubility of solutes in solvents being key determinants of extraction efficiency [57]. Any condition that enhances solute diffusion or dissolution in solvents can improve extraction rates. Traditional extraction methods, such as maceration, percolation, decoction, and reflux, typically involve the use of large volumes of water or organic solvents under normal pressure, resulting in prolonged extraction times and low extraction efficiencies.

In recent years, the emergence of novel technologies for natural product extraction and separation has led to improved yields and purities of active ingredients through the application of auxiliary means such as pressure. Innovative techniques, including microwave-assisted extraction [58], enzyme-assisted extraction [59], supercritical fluid extraction [60], ionic liquid extraction, and high-speed countercurrent extraction [61], have been creatively applied in natural product extraction and separation. These methods offer advantages such as reduced solvent consumption, shorter extraction times, and enhanced selectivity.

The identification of active compounds is a critical step in natural product research and drug discovery, with the prediction of macromolecular targets, associated biological activities, and potential toxicity of natural products being of particular importance. In traditional research, active natural products are primarily isolated and screened from natural sources, such as plants, animals, and microorganisms, using bioactivity-guided fractionation methods. Natural extracts are fractionated using chromatographic techniques, and their chemical properties are elucidated through analytical methods such as mass spectrometry and nuclear magnetic resonance [62].

At the beginning of the 21st century, the rapid development of genome sequencing and various omics technologies enabled researchers to predict the natural products that organisms may produce by analyzing their genomic data using strategies such as genome mining. In recent years, artificial intelligence (AI) technology has made significant progress in predicting compound structures and biological activities, greatly expanding the scope of natural product research [63]. For instance, deep learning algorithms have been employed to directly predict the skeletal structures of natural products from biosynthetic gene cluster sequences [64], while graph convolutional neural network (GCN) algorithms have been utilized to predict the pharmacological activities and targets of natural products [65]. These advancements have greatly accelerated the discovery of natural products, and the development and application of drugs derived from them.

With strong biocompatibility and high potential for chemical structure modification, natural products enable effective interactions with biological targets, showcasing remarkable pharmacological activity [66]. Natural products possess diverse pharmacological activities and advantages, including multicomponent and multitarget properties, stable therapeutic effects, and low toxicity. In recent years, research in this field has gained significant momentum. Screening for natural bioactive compounds targeting AD from natural sources has become a pivotal strategy in the development of anti-AD drugs, leading to numerous promising results. Compounds such as flavonoids, alkaloids, polysaccharides, and saponins have demonstrated anti-AD potential by modulating pathways related to Aβ, tau, and other mechanisms, underscoring the potential of natural bioactive compounds as a valuable reservoir for AD therapeutics.

Flavonoids targeting tau protein for the treatment of Alzheimerʼs disease

Flavonoids are a class of compounds synthesized via the phenylalanine pathway, often found in plants as glycosides combined with sugars or in their free form. Modern pharmacological studies have highlighted the ability of flavonoids to improve cognitive dysfunction in AD model animals, alleviate symptoms through multiple targets, and slow disease progression. Icariin, an 8-isopentenyl flavonoid glycoside and the main active ingredient in Herba Epimedii, has been shown to enhance brain mitochondrial energy metabolism in AD models, likely through the PI3K/AKT/GSK-3β signaling pathway. It also regulates brain signaling and amyloid precursor protein (APP) processing pathways, inhibiting Aβ deposition and tau phosphorylation [48], [67]. Puerarin has demonstrated the capacity to significantly ameliorate the behavioral performance deficits observed in rats subjected to D-galactose-induced aging. Furthermore, this isoflavone has been shown to augment neurogenesis and attenuate the hyperphosphorylation of the microtubule-associated protein tau within the hippocampal region. Mechanistic investigations have revealed that puerarin exerts its effects through modulation of the FGF-2/GSK-3 signaling cascade. Collectively, these findings suggest that puerarin may hold promise as a potential therapeutic agent for the treatment of age-related neurodegenerative disorders [68]. Nobiletin (NOB), a hexamethoxyflavone, reduces reactive oxygen species (ROS), modulates the PI3K/AKT, MAPK, and NF-κB pathways, suppresses neuroinflammation, alleviates cholinergic neurodegeneration, and reduces the pathological deposition of Aβ and tau, exerting potent anti-AD effects [69]. Flavonoids from the stems and leaves of Scutellaria baicalensis Georgi exhibit antibacterial, anti-inflammatory, and antiaging properties, protecting the heart and brain while improving learning and memory impairments. These compounds significantly enhance cognitive functions in various AD models, including those induced by D-galactose, okadaic acid, cerebral ischemia, and compound Aβ. They inhibit NFT deposition and tau protein hyperphosphorylation, significantly reducing the expression of p-tau at sites such as Thr181, Thr217, Thr231, Ser199, Ser235, Ser396, and Ser404 in rat brains [70]. Research has also shown that Erigeron breviscapus and its active ingredients, scutellarin and caffeoylquinic acid, enhance learning and memory by inhibiting Aβ production, mitigating oxidative stress and inflammation, and suppressing tau protein hyperphosphorylation. Scutellarin, a flavonoid compound, is particularly effective in these processes [71]. Rutin, a representative flavonoid, exhibits free radical scavenging activity and suppresses APP and BACE1 expression, treating AD by inhibiting p-tau production and aggregation [72]. Quercetin, another extensively studied bioflavonoid, regulates intestinal flora, alleviates brain inflammation, reduces insulin resistance, and diminishes Aβ aggregation and tau phosphorylation, showing neuroprotective effects against AD [73]. Kaempferol (KMP), structurally similar to quercetin, mitigates oxidative stress and inflammation, reduces Aβ-induced neurotoxicity, and modulates the cholinergic system to improve AD symptoms. Clinical studies have confirmed its anti-AD activities, including neural plasticity promotion and antagonism of Aβ, tau, inflammation, and oxidation [74]. Total flavonoids and ginkgolides in Ginkgo biloba extract EGB761 have shown significant anti-AD effects, enhancing neural plasticity, reducing Aβ production, lowering TNF-α and interleukin-1β (IL-1β) secretion by microglia, and preventing caspase-3 activation. These effects result in notable improvements in the cognitive functions of dementia rat models [75]. In summary, various natural flavonoids demonstrate effective therapeutic potential against tau phosphorylation associated with AD, as detailed in [Table 1].

Table 1 The mechanisms of flavonoids regulating tau protein.

Numbers	Compounds	Chemistry structure	Models	Dosages	Activities	Molecular mechanisms	References
Note: ↓ reduced activity; ↑ enhanced activity; – not mentioned in the text
1	Icariin		NaN3-induced neuronal PC12 cell; okadaic acid-induced SH-SY5Y cells	0.01 – 1 µM; 2.5, 1 µM	p-Tau↓, GSK-3β↓; tau phosphorylation sites: Ser396, Ser404, Thr217	Reduce tau protein phosphorylation by activating the PI3K/AKT/GSK-3β signaling pathway.	[48], [67]
2	Puerarin		D-galactose induced SD rats	40, 80, 160 mg/kg/day	pS9-GSK-3β↑, p-tau↓; tau phosphorylation sites: Ser199, Ser202	Effectively slowing down the increase in tau protein phosphorylation levels by reducing GSK-3β activity levels.	[68]
3	Nobiletin		SAMP8 mice	10, 50 mg/kg/day	p-Tau↓; tau phosphorylation sites: Ser396, Ser202, Thr205, Thr231	Improve age-related cognitive impairment and reduces oxidative stress and tau phosphorylation.	[69]
4	Flavonoids from Scutellaria baicalensis Georgi (SSF)		Aβ 25 – 35 and AlCl3 combined with RHTGF-β1-induced SD rats	35, 70, 140 mg/kg/day	p-Tau↓; tau phosphorylation sites: Thr 181, Thr 217, Thr 231, Ser 199, Ser 235, Ser 396, Ser 404	Inhibit hyperphosphorylation of tau protein, then protecting neurons from damage and improve the impaired memory.	[70]
5	Scutellarin		L-glutamic acid-damaged HT22 cell apoptosis model; aluminum chloride plus D-galactose-induced AD mouse	5, 15 µM; 20 mg/kg/day	Caspase-3↓, Aβ 1 – 42↓, p-tau↓	The protective effects are associated with its antioxidant and antiapoptotic properties.	[71]
6	Rutin		Tau-P301S mice	100 mg/kg/day	IL-1β↓, TNF-α↓, IKK-β↓, p-P65/P65↓, PP2A↑, p-tau↓	Reduce pathological tau levels, regulate tau hyperphosphorylation by increasing PP2A levels, and inhibit glial cell proliferation and neuroinflammation by downregulating the NF-κB pathway.	[72]
7	Quercetin		Okadaic acid-induced AD mice	plasma exosomes (Exo-Que), 0.6 mg of Que per mL	CDK5↓, p-tau↓, caspase-9↓, caspase-3↓	Reduce the phosphorylation level of tau protein and inhibit NFT formation.	[73]
8	Kaempferol		–	–	PI3K and/or AKT↑, GSK-3β↓, p-tau↓; tau phosphorylation site : Ser396	Reverse neuroinflammation through the PI3K/AKT pathway, and counteract Aβ-mediated tau hyperphosphorylation by inhibiting GSK-3β.	[74]
9	EGb761	–	Hyperhomocysteinemia (HHcy) injected in rats	400 mg/kg/day	GSK-3β↓, PP2A↑; tau phosphorylation sites: Thr231, Ser262, Ser396, Ser404	Treat AD through its antioxidative activity and decreasing tau hyperphosphorylation in addition to the protection against Aβ-induced neurotoxicity.	[75]

Alkaloids targeting tau protein for the treatment of Alzheimerʼs disease

Alkaloids, nitrogen-containing basic compounds primarily derived from plants, encompass a subset of nitrogenous organic molecules with significant biological activity but lacking basicity. Modern pharmacological research highlights their therapeutic potential in AD through diverse mechanisms, including anti-neuroinflammatory, antioxidant effects, inhibition of Aβ aggregation, and suppression of tau protein phosphorylation. Representative active compounds include evodiamine, berberine, ligustrazine and its derivatives, and gelsemine, among others ([Table 2]). Rutaecarpine (Rut), an indole quinoline alkaloid extracted from the nearly mature fruit of Evodia rutaecarpine, exhibits neuroprotective properties in the central nervous system and enhances learning and memory in mouse models of cerebral ischemia/reperfusion injury. Studies have shown that Rut administration reduces tau protein phosphorylation at Thr205 and Ser214 sites induced by high glucose [76]. Berberine (BBR), a natural isoquinoline alkaloid, is clinically utilized to treat neurodegenerative disorders such as Alzheimerʼs, Parkinsonʼs, and Huntingtonʼs diseases. In vivo studies demonstrate that BBR improves learning and memory in various AD animal models, inhibits tau protein hyperphosphorylation via PP2A activation and GSK-3β inhibition, and reduces NFT formation by modulating the AKT/GSK-3β signaling pathway [77], [78]. Ligustrazine, an alkaloid isolated and purified from Ligusticum chuanxiong Hort of the Umbelliferae family, has been extensively investigated for its therapeutic benefits in myocardial and cerebral infarction. Clinically, ligustrazine is employed in China and Southeast Asia for the prevention and treatment of neurodegenerative, cardiovascular, and cerebrovascular diseases. Research indicates that ligustrazine lowers p-tau levels at multiple sites, including tau-5, pS202, and pS396. Furthermore, ligustrazine derivatives inhibit tau protein phosphorylation and facilitate the clearance of tau accumulation by suppressing excessive JNK signaling pathway activation or enhancing autophagy [79]. Gelsemine, an oxindole alkaloid, exhibits neuroprotective, anxiolytic, and analgesic effects in various conditions. Studies reveal its capacity to mitigate neuroinflammation, increase postsynaptic protein expression, and potentially reduce tau hyperphosphorylation by inhibiting GSK-3β [80]. However, the longstanding toxicity concerns surrounding gelsemine warrant further safety investigations. Isorhynchophylline ameliorates cognitive deficits by inhibiting JNK signaling pathway activation, thereby reducing Aβ production and aggregation, tau hyperphosphorylation, and neuroinflammation. Its neuroprotective effects are closely associated with the inhibition of tau hyperphosphorylation and activation of the PI3K/AKT signaling pathway [81]. Huperzine A, approved in China for symptom management in AD, primarily functions as an AChE inhibitor. Preclinical studies reveal that, beyond AChE inhibition, it alleviates mitochondrial dysfunction, regulates APP processing, reduces hippocampal Aβ accumulation, and decreases the Aβ-ABAD complex. Additionally, in APPsw cell models and APP/PS1 transgenic mice, huperzine A modulates Wnt signaling, inhibits GSK-3β activity, and stabilizes β-catenin protein levels [82].

Table 2 The mechanisms of alkaloids regulating tau protein.

Numbers	Compounds	Chemistry structure	Models	Dosages	Activities	Molecular mechanisms	References
Note: ↓ reduced activity; ↑ enhanced activity
1	Rutaecarpine		High-glucose-induced C57BL/6 mice	0.01%	pS9-GSK-3β↑, GSK-3β↓, p-tau↓; tau phosphorylation sites: Thr205, Ser214	Reduced tau hyperphosphorylation through downregulating GSK-3β activity.	[76]
2	Berberine		APP/PS1 mice; 3×Tg AD mice	50, 100 mg/kg/day	AKT↑, GSK-3β↓, PP2A↑; tau phosphorylation sites: Ser199, Ser202, Thr205, Thr231, Ser396, Ser404	Decreased the hyperphosphorylated tau protein, lowered the activity of NF-κB signaling. Promoted autophagic clearance of tau by enhancing the activity of autophagy via the class III PI3K/beclin-1 pathway.	[77], [78]
3	Ligustrazine		Hyperhomocysteinemia-induced AD rat	60 mg/kg, 14 days	PI3K/AKT/GSK-3β↑, JNK↓, p-tau↓; tau phosphorylation sites: Ser199, Ser396	Reduce the level of p-tau and inhibit the phosphorylation function of tau protein.	[79]
4	Gelsemine		Aβ 1 – 42-induced Institute of Cancer Research (ICR) mice	5, 10 µg/kg/day	pS9-GSK-3β↑, p-tau↓; tau phosphorylation site: Ser396	Prevent Aβ oligomer-induced tau hyperphosphorylation and PSD-95 reduction, possibly via attenuating neuroinflammation and inhibiting GSK-3β.	[80]
5	Isorhynchophyllie		TgCRND8 mice	20, 40 mg/kg/day	p-c-Jun/c-Jun↓, p-JNK/JNK↓, p-tau↓; tau phosphorylation sites: Ser396, Thr205	By inhibiting the activation of the JNK signaling pathway, the production and deposition of Aβ, excessive phosphorylation of tau protein, and neuroinflammation are reduced.	[81]
6	Huperzine A		SH-SY5Y cells	0, 0.1, 1, and 10 µM	p-GSK-3β/GSK-3β↑, pS9-GSK-3β↑, p-tau↓, p-tau/tau↓	Affects the GSK-3β and tau pathways by downregulating the GSK-3β activity and the phosphorylation of tau.	[82]

Saponins targeting tau protein for the treatment of Alzheimerʼs disease

Saponins are glycoside compounds formed by the condensation of saponin ligands with sugars, glucuronic acids, etc. Structurally, they are classified into steroidal saponins and triterpenoid saponins. Among these, Panax notoginseng and ginsenosides are the primary saponins reported for the treatment of AD ([Table 3]). Modern pharmacological studies reveal that saponins mitigate brain damage associated with AD through mechanisms such as reducing Aβ aggregation, decreasing tau protein phosphorylation, counteracting oxidative stress, preventing neuronal damage, and regulating acetylcholine metabolism. Ginseng is a critical therapeutic agent for AD, with its saponins serving as key active components. The mechanisms underlying the therapeutic effects of ginsenosides on AD have been extensively investigated. Ginsenoside Rg1 protects neurons by modulating signaling pathways, including PI3K/AKT, ERK/MAPK, NF-κB, and GSK-3β/tau. It exerts anti-Aβ toxicity, anti-inflammatory, antiapoptotic, and antioxidative effects, alongside neurotransmitter regulation, by downregulating NF-κB signaling and inhibiting AKT and ERK1/2 activation. Furthermore, Rg1 reduces phosphorylated tau levels and prevents Aβ formation in the brain via the GSK-3β/tau signaling pathway [83]. Both in vivo and in vitro studies demonstrate that ginsenoside Rg2 possesses preventive and therapeutic effects against AD. It reduces Aβ accumulation in AD rat brains, enhances choline acetyltransferase (ChAT) activity, improves cognitive function, and regulates neuronal apoptosis by increasing Bcl-2 expression, decreasing Bax expression, and upregulating C-fos [84]. Ginsenoside Rb1 reverses tau hyperphosphorylation and restores p-GSK3 and PP2A levels by activating the PI3K pathway, thereby increasing AKT phosphorylation and reducing GSK-3β activity. Similarly, ginsenoside Rd inhibits GSK-3β expression and activity, enhances PP2A activity, and decreases tau hyperphosphorylation [85]. Ginsenosides Rg3 and Rg5 protect against apoptosis induced by Aβ25 – 35, reduce Aβ deposition, and lower TNF-α and IL-1β levels in brain tissue. Ginsenoside Re activates the Nrf2 antioxidant signaling pathway, mitigating oxidative stress caused by Aβ25 – 35. These diverse ginsenoside components demonstrate significant therapeutic potential against AD through multiple pathways [52], [86]. P. tenuifolia exhibits antioxidant, antiaging, and cognitive-enhancing effects, with its primary active ingredient, polygala saponin, demonstrating the ability to inhibit Aβ toxicity, reduce tau phosphorylation, alleviate oxidative stress, prevent neuronal apoptosis, and maintain calcium homeostasis. Polygala saponin acts on multiple targets to slow neuronal degeneration, ameliorate memory deficits, and effectively prevent and treat AD [87]. Additional research shows that polygala saponins enhance O-GlcNAc glycosylation, reduce tau phosphorylation sites, and ultimately lower p-tau levels. Saponins derived from Anemarrhena asphodeloides, another key active compound, reduce NFT formation by decreasing p-tau expression. Moreover, these saponins exert anti-AD effects by increasing ChAT activity and modulating cholinergic function [88], [89].

Table 3 The mechanisms of saponins regulating tau protein.

Numbers	Compounds	Chemistry structure	Models	Dosages	Activities	Molecular mechanism	References
Note: ↓ reduced activity; ↑ enhanced activity
1	Ginsenoside Rg1		Okadaic acid-induced SD rats; Aβ 25 – 35 and D-galactoseinduced	20 mg/kg/day	PP2A↑, p-tau↓; rau phosphorylation sites: Ser396, Thr231	Reduce memory impairment and weaken the formation of Aβ through the GSK-3β/tau signaling pathway.	[83]
2	Ginsenoside Rg2		3 xTg-AD mice	198.4 mg/kg/day	Aβ 25 – 35↓, TNF-α↓, IL-1β↓, IL-6↓, p-ERK/ERK↑and p-MAPK/MAPK↑, p-tau↓; tau phosphorylation site: Ser422	The neuroprotective effects of Rg2 may be related to the MAPK-ERK pathway.	[84]
3	Ginsenoside Rb1		Aluminum chloride-induced ICR mice	20 mg/kg/day	P-GSK3↓, PP2A↑; tau phosphorylation site: Ser396	Reverse hyperphosphorylation of tau by regulating p-GSK3 and PP2A levels.	[85]
4	Ginsenoside Rd		MCAO-induced SD rats	30 mg/kg before MCAO and 10 mg/kg/day	PKB/AKT↓, GSK-3β↓, p-tau↓; tau phosphorylation sites: Ser199, Ser202, PHF-1	Reduce tau phosphorylation via the PI3K/AKT/GSK-3β pathway.	[52], [86]
5	Tenuigenin		STZ-induced SD rats	2, 4, 8 mg/kg/day	p-Tau↓; tau phosphorylation sites: ser396, thr181	Improve cognitive impairment, oxidative stress, and tau protein hyperphosphorylation.	[87]
6	Sarsasapogenin		STZ-induced SD; high glucose-cultured SH-SY5Y cells	20, 60 mg/kg/day; 0.1, 1, 10 µM	p-GSK-3β↑, p-AKT ↑, p-tau↓; tau phosphorylation sites: Ser404, Ser202	Alleviate diabetes encephalopathy by activating the PPARγ signaling pathway and inhibiting the overproduction of Aβ and p-tau.	[88]
7	Saikosaponin C		Aβ-induced SH-SY5Y cells	3, 10 µM	p-Tau↓; tau phosphorylation sites: AT180 (Thr231), PHF-13 (Ser396)	Inhibits abnormal phosphorylation of tau protein and production of amyloid beta, thereby promoting synaptic integrity.	[89]

Polysaccharides targeting tau protein for the treatment of Alzheimerʼs disease

Polysaccharides are chain polymers essential for sustaining life activities. Biologically active polysaccharides are predominantly found in fungi, algae, and rhizome medicinal herbs. Studies have identified several polysaccharides with anti-AD properties, including S. chinensis polysaccharide, A. sinensis polysaccharide, Lycium barbarum polysaccharide, Poria cocos polysaccharide, Polygonatum sibiricum polysaccharide, Cistanche deserticola polysaccharide, and Cornus officinalis polysaccharide. Their ability to ameliorate memory impairment is closely associated with regulating cholinergic system function, combating oxidative stress, and reducing inflammation. S. chinensis acidic polysaccharide (SCP-A), an acidic component isolated from the total polysaccharides of S. chinensis, has demonstrated significant therapeutic potential. In an AD mouse model induced by Aβ _{25 – 35}, SCP-A was found to increase the phosphorylation of GSK-3β at the Ser9 site while reducing its expression at the Tyr216 site, ultimately improving learning and memory functions [90]. Astragalus membranaceus, a medicinal herb with over 2000 years of documented use, contains polysaccharides as its primary active constituents. These polysaccharides exhibit diverse effects, including blood sugar reduction, antitumor activity, and anti-inflammatory properties. Experimental studies have confirmed that Astragalus polysaccharides regulate key proteins such as p-tau, PP2A, and GSK-3β in the hippocampus, thereby mitigating AD-related pathology [91]. Similarly, Codonopsis pilosula polysaccharides enhance PP2A activity and reduce tau phosphorylation at multiple sites, highlighting their potential in AD treatment [92]. In summary, polysaccharide-based active substances offer neuroprotective, antioxidative, anti-inflammatory, antiaging, and immune-enhancing benefits, with promising applications in the prevention and treatment of AD. Other polysaccharides may also operate through similar mechanisms, notably by inhibiting tau hyperphosphorylation via GSK-3β regulation [93], [94], [95]. This insight broadens the scope for exploring natural products as potential therapeutic agents for AD ([Table 4]).

Table 4 The mechanisms of polysaccharides regulating tau protein.

Numbers	Compounds	Models	Dosages	Activities	Molecular mechanism	References
Note: ↓ reduced activity; ↑ enhanced activity
1	Schisandra chinensis polysaccharose	Aβ 25 – 35-induced male SD rats	38.15 mg/kg/day	AchE↓, GSK-3β↓, NOS↓, SOD↑	Reduce the phosphorylation level of tau protein, Aβ deposition, and oxidative damage in AD rats, and reverse the changes in AD neurotransmitters.	[90]
2	Astragalus polysaccharide (APS)	Aβ 25 – 35-induced SD rats	400 mg/kg/day	APP↓, Aβ↓, p-tau↓, GSK-3β↓ and BACE1↓, PP2A↑	Improving the positioning, navigation, learning, and memory abilities of rats has a protective effect on AD.	[91]
3	Codonopsis pilosula polysaccharide (CPP)	HEK 293/tau cells; AAV2-h infected mice	50, 100, 200 µg/mL	PP2A↑, p-tau↓; tau phosphorylation sites: Ser199, Ser202/Thr205 (AT8), Thr231	By activating PP2A, excessive phosphorylation of tau protein is achieved, and cognitive function in AD is impaired and weakened by restoring synaptic plasticity and synaptic development.	[92]
4	Lycium barbarum polysaccharide	ICV-STZ-induced C57BL/6 J mice	50, 100, 200 mg/kg/day	p-Tau↓; tau phosphorylation sites: Ser199, Thr205, Ser396, Ser404	Regulate the expression of proteins related to the IRS1/PI3K/AKT signaling pathway, thereby reducing Aβ deposition and tau protein phosphorylation.	[93]
5	Poria cocos polysaccharide	D-galactose and aluminum trichloride-induced rats	100, 200, 300 mg/kg/day	p-IKBα↓, p-NF-κB↓, p-ERK↓, p-38↓	It exerts a certain neuroprotective effect by reducing oxidative stress, cell apoptosis, inflammatory response, and inhibiting the MAPK/NF-κB pathway.	[94]
6	Dendrobium officinale polysaccharide (DOP)	SAMP8 and SAMR1 mice	40 mg/kg/day	Aβ 42↓, p-tau↓; tau phosphorylation sites: Ser396, Ser404	By regulating the activation of microglia, there is neuroprotection against cognitive impairment, and the accumulation of Aβ 42 and tau phosphorylated proteins is also reduced.	[95]

Phenols targeting tau protein for the treatment of Alzheimerʼs disease

Oxidative stress and free radical accumulation are hallmark features of AD, particularly in its early stages. Due to the phenolic hydroxyl groups in their chemical structure, phenolic compounds possess strong antioxidant properties ([Table 5]). These compounds effectively scavenge free radicals, reduce oxidative stress, modulate inflammatory factor expression, and alleviate brain inflammation. Such actions help prevent neuronal loss and slow the progression of neurodegenerative diseases. Research conducted by an Indian team revealed that catechins, a class of phenolic compounds, regulate the pathological link between ferroptosis and AD. Catechins promote tau protein phosphorylation, inhibiting the formation of abnormal tau aggregates and mitigating AD-associated multifaceted toxicity [96]. Additionally, polyphenolic compounds have been shown to improve mitochondrial dysfunction through the modulation of the PI3K/AKT signaling pathway. Curcumin, a polyphenolic compound with diverse pharmacological properties, has been extensively studied for its ability to inhibit tau protein hyperphosphorylation. Curcumin suppresses tau kinases GSK-3β and CDK5, thereby reducing Aβ-induced tau hyperphosphorylation. Furthermore, curcumin activates autophagy and upregulates BCL2-associated athanogene 2 (BAG2), reducing dimer tau levels and facilitating pathological tau clearance [97]. Stilbene glucoside, an active component extracted from P. multiflorum Thunb., has completed phase II clinical trials and is undergoing phase III trials for the treatment of mild to moderate AD. Stilbene glucoside inhibits presenilin-1 expression, decreases APP and Aβ production in the brain, elevates PP2A and microtubule-associated protein 2 (MAP-2) levels in the hippocampus, promotes p-tau dephosphorylation, and reduces NFT formation [98], [99]. Gastrodin, another phenolic compound, alleviates inflammatory responses via modulation of the Nrf2/HO-1 signaling pathway. It also activates the p38 MAPK/Nrf2 pathway to mitigate oxidative stress, thereby lowering tau protein phosphorylation levels in AD mouse brains and protecting neurons [100]. Rhodiola rosea, a traditional Tibetan medicine, has broad therapeutic applications in the cardiovascular and nervous systems, as well as in liver and skin conditions. Its primary active ingredient, salidroside, mitigates Aβ-induced neurotoxicity, suppresses inflammatory responses, prevents AD and vascular dementia, and reduces tau hyperphosphorylation, demonstrating neuroprotective effects [101]. Verbascoside also exhibits neuroprotective properties by blocking NF-κB to suppress neuroinflammation, activating the ERK1/2-Nrf2 pathway, reducing Aβ deposition and abnormal tau phosphorylation, and inhibiting neuronal apoptosis [102].

Table 5 The mechanisms of phenolic compounds regulating tau protein.

Numbers	Compounds	Chemistry structure	Models	Dosages	Activities	Molecular mechanism	References
Note: ↓ reduced activity; ↑ enhanced activity; – not mentioned in the text
1	Polycatechol	–	Aβ 42-induced neuronal cell	20 µg/mL	NFTs↓, p-tau↓	Inhibit iron toxicity, counteract amyloid toxicity, and regulate tau LLPS.	[96]
2	Curcumin		High-fat feeding combined with STZ	200 mg/kg/day	SOD↑, MDA↓, p-AKT↑, p-AMPK↑, and p-GSK-3β↑, p-tau↓	Possible alleviation of oxidative damage and reduction of tau protein phosphorylation levels through the AKT/AMPK/GSK-3β pathway.	[97]
3	2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glycoside, TSG		Aβ 25 – 35-induced SD rats; APP/PS1/tau transgenic dementia mice	100, 200, 300 mg/kg/day	Regulate several different molecules, such as Akt, AMPK, CaMKII, ERK1/2, SIRT1, NF-κB, CREB, and Nrf2	Reduce oxidation, regulate neuroinflammation, prevent cell apoptosis, and promote neurogenesis and synaptic development.	[98], [99]
4	Gastrodin/gastrodine, GAS		Aβ 1 – 42-induced Kunming mice	100 mg/kg/day	Aβ↓, tau↓, p-tau↓; BDNF↑, PSD-95↑, synaptophysin (SYN)↑	Reduce the phosphorylation level of tau protein by reducing oxidative stress, thus protecting neurons.	[100]
5	Salidroside (Sal)		Tau transgenic drosophila line	2, 6, 20 µM	p-GSK-3β↑, p-tau↓	Relieve behavioral and neurodegenerative pathological changes, inhibit neuronal loss; its mechanism is related to upregulating GSK-3β phosphorylation and reducing tau protein hyperphosphorylation.	[101]
6	Acteoside		APP/PS1 mice	50, 100 mg/kg/day	Aβ40↓, Aβ42↓GSK-3β↓, p-tau↓; tau phosphorylation sites: Thr181, Ser202, Thr231, Ser396	Relieve anxiety and improve cognitive impairment, significantly increase the degradation of Aβ and inhibit the excessive phosphorylation of tau.	[102]

Phenylpropanoids targeting tau protein for the treatment of Alzheimerʼs disease

Phenylpropanoids are naturally occurring compounds composed of C6-C3 groups, typically featuring a phenolic structure and are classified as phenolic substances. This category encompasses simple phenylpropanoids, coumarins, and lignans. Notably, coumarin drugs share a similar structure with vitamin K. Lignans, found in plants, exhibit free radical scavenging and antioxidant properties. Schizandrin A (SCH), a lignan extracted from the dried and mature fruits of S. chinensis, a member of the Magnoliaceae family, is deemed effective in the prevention and treatment of AD. Evidently, SCH can hinder Aβ _1 – 42-induced neuronal damage in AD. By activating the PI3K/AKT signaling pathway, it upregulates p-AKT activity, subsequently reducing downstream p-GSK-3β activity and tau protein levels [103]. Research indicates that honokiol exerts neuroprotective effects in various animal models. Studies have employed nanoparticle drug delivery to enhance the bioavailability of honokiol, confirming its ability to inhibit β-secretase, thereby regulating the processing of APP, mitigating tau hyperphosphorylation, reducing neuroinflammation, and significantly ameliorating cognitive impairment [104]. Osthole (OST) is a coumarin compound found in Angelica pubescens. Research has shown that OST can improve spatial memory impairment in AD animal models. It is believed to have a potential neuroprotective effect by regulating the PI3K/Akt/GSK-3β signaling pathway and reversing tau hyperphosphorylation [105]. Ferulic acid is also a phenylpropanoid compound with anti-AD activity. Studies have demonstrated that ferulic acid can inhibit the production of APP, reduce Aβ aggregation, regulate the phosphorylation of GSK-3β protein, and suppress the expression of the proapoptotic protein caspase-9, thereby exerting a neuroprotective effect [106]. Trans-cinnamaldehyde, which is found in plants such as cinnamon, can reduce the level of p-tau in the brains of AD mice, inhibit neuroinflammation, and enhance synaptic function [107]. In the future, these natural phenylpropanoids may emerge as a novel strategy for treating p-tau in AD ([Table 6]).

Table 6 The mechanisms of phenylpropanoids regulating tau protein.

Numbers	Compounds	Chemistry structure	Models	Dosages	Activities	Molecular mechanism	References
Note: ↓ reduced activity; ↑ enhanced activity
1	Schisandrin		Aβ 1 – 42 exposed SH-SY5Y cell	10 µmol/L	p-Akt↑, p-tau↓, p-GSK-3β↓	Reducing tau protein phosphorylation is associated with activation of the PI3K/AKT signaling pathway.	[103]
2	Honokiol		TgCRND8 mice	20 mg/kg/day	p-Tau/tau↓, caspase-3↓, Bcl-2↑; p-JNK/JNK↓, p-35/CDK5↓, p-GSK-3β/GSK-3β↑; tau phosphorylation sites: Thr205, Ser396	Inhibiting Aβ deposition, tau hyperphosphorylation, and neuroinflammation through suppressing the activation of the JNK/CDK5/GSK-3β signaling pathway.	[104]
3	Osthole		6-month-old APP/PS1 mice	20 mg/kg/day	p-Tau↓, PI3K↑, p-AKT/AKT↑, p-GSK-3β/GSK-3β↑; tau phosphorylation site: Ser202	Decrease phosphorylated tau levels via activation of the PI3K/AKT/GSK-3β signaling pathway.	[105]
4	Ferulic acid		SH-SY5Y cell model overexpressing APP;Aβ 42-induced SD rats	0.625 ~ 10 µmol/L; 1.5,3,6,g/kg/day	Cell viability↑, Aβ 40↓, caspase-3/7↓, p-tau↓	Reduce tau protein phosphorylation and exert anti-neuronal apoptosis effects by regulating the expression of GSK-3β and inhibiting caspase-9.	[106]
5	Trans-cinnamaldehyde		PS cDKO mice	240 ppm	MAP2↑, SYP↑, PSD-95↑, p-αCaMKII↑, p-tau↓	Reverse the abnormal expression of synaptic proteins and excessive phosphorylation of tau protein in the hippocampus and prefrontal cortex, improve NMDA receptor dysfunction, and inhibit neuroinflammatory responses.	[107]

Terpenoids targeting tau protein for the treatment of Alzheimerʼs disease

Natural products contain numerous terpenoid compounds, which have been extensively studied for their potential in treating AD ([Table 7]). Among these, iridoid glycosides, a class of monoterpenes with chiral carbon atoms, exhibit diverse biological activities. Most iridoid glycosides investigated for AD are derived from C. officinalis, with cornuside being one of its primary active components. Research indicates that cornuside possesses anti-inflammatory, antiapoptotic, and oxidative stress-ameliorating properties. Its pharmacological effects are primarily mediated through inhibition of ERK1/2 phosphorylation and the IκBα/NF-κB signaling pathway, reducing the secretion of proinflammatory factors [108], [109]. Paeoniflorin, another terpenoid compound, exhibits various biological effects, including anti-inflammatory, hypoglycemic, antithrombotic, anticonvulsant, cardiac protective, antitumor, and immune-regulating properties. Recent studies highlight its relevance to nervous system diseases, showing that paeoniflorin reduces β-amyloid plaque deposition, inhibits astrocyte activation, and decreases IL-1β and TNF-α expression, offering neuroprotection against AD [110]. Tanshinone ⅡA, widely used in cardiovascular treatments, has demonstrated significant anti-AD effects in both in vivo and in vitro studies. It facilitates Aβ transport, reduces tau protein phosphorylation, reverses cholinergic system dysfunction, and mitigates oxidative stress, inflammation, and apoptosis [111]. Proanthocyanidins, oligomeric compounds composed of catechin and epicatechin subunits, have demonstrated the capacity to mitigate the pathological hallmarks of AD, specifically extracellular amyloid deposition and NFTs. The mechanisms underlying these effects involve the attenuation of Aβ accumulation and the modulation of tau pathology [112]. Artemisinin, traditionally an antimalarial drug, enhances cognitive abilities in AD models by downregulating pathological protein expression, reducing Aβ and tau accumulation, and suppressing inflammatory and apoptotic responses. Its antioxidant and anti-inflammatory properties further protect neuronal cells [113]. Patchouli alcohol, another terpenoid compound, modulates APP processing to prevent Aβ plaque deposition. It alleviates tau hyperphosphorylation, neuroinflammation, and gut microbiota imbalances, while improving anxiety-related behaviors and cognitive impairments in AD mice [114]. Triptolide, derived from the root bark of Tripterygium wilfordii, activates the transcription factor EB (TFEB)-mediated autophagy-lysosome pathway, promoting the degradation of p-tau aggregates. This action effectively alleviates memory deficits associated with AD [115]. These terpenoid compounds exhibit multifaceted mechanisms, including anti-inflammatory, antioxidant, and autophagy-regulating effects, making them promising candidates for AD therapy.

Table 7 The mechanism of terpenoids regulating tau protein.

Numbers	Compounds	Chemistry structure	Models	Dosages	Activities	Molecular mechanism	References
Note: ↓ reduced activity; ↑ enhanced activity; – not mentioned in the text
1	Cornus officinalis iridoid glycosides (CIG)		rTg4510 mice; wortmannin and GF-109203X (GFX)-induced rats; SK-N-SH cells	5, 100, 200 mg/kg/day; 60, 120 mg/kg/day	PTPA↑, PP2A↑, p-tau↓, GSK-3β↓	Promote the PI3K/AKT and PP2A signaling pathways to inhibit GSK-3β activity, enhance PP2A activity by preventing PME-1-induced PP2Ac demethylation, and regulate GSK-3β/PP2A cross talk, thereby suppressing tau hyperphosphorylation.	[108], [109]
2	Paeoniflorin		Okadaic acid-induced SH-SY5Y cells; diabetic rats induced by a high-sucrose, high-fat diet and low dose of streptozotocin (STZ)	50, 100, 200 µM; 15, 30 mg/kg/day	p-AKT↑, p-GSK-3β↑, p-tau↓	Decreased hyperphosphorylated tau via the calpain/AKT/GSK-3β-related pathway. Prevent tau hyperphosphorylation and protect cognitive impairment by restoring the SOCS2/IRS-1 signal pathway.	[110]
3	Tanshinone IIA		Aβ 1 – 42-induced SD rats	–	P-ERK1/2↓, GSK-3β↓, p-tau↓; tau phosphorylation sites: Ser396, Ser404, Thr205	Improving learning and memory ability in AD therapy with mechanisms involving the ERK and GSK-3β signal pathway.	[111]
4	Procyanidins		SH-SY5Y cells	–	p-PKA↑, p-CaMKIV↑, p-MAPK, p-CREB↑, p-tau↓	Affect the transcription of SIRT1 gene and inhibit tau acetylation to reduce tauopathies.	[112]
5	Artemisinin		3 xTg-AD mice; SH-SY5Y cells	1, 5, 10 mg/kg/day; 3.125 – 200 µM	ERK/CREB↑	Aβ deposition decreased and phosphorylated tau levels significantly decreased.	[113]
6	Patchouli alcohol		STZ-induced AD rats	25, 50 mg/kg/day	SIRT1↑, p-tau↓; tau phosphorylation sites: Thr181, Thr205, Ser396, Ser404	Improving cognitive and memory impairment involves alleviating the SIRT1 and NF-κB pathways by regulating neuroinflammation, tau pathology, and Aβ deposition.	[114]
7	Celastrol		P301S tau and 3 xTg mice	1, 2 mg/kg/day	TFEB↑, tau↓, conformation-specific tau (MC1)↓, p-tau↓; tau phosphorylation sites: Ser396, Ser404	Enhancing TFEB-mediated autophagy and lysosomal biogenesis, reducing phosphorylated tau aggregates, and weakening memory and cognitive impairments.	[115]

Discussion and Conclusion

Tau protein undergoes extensive post-translational modifications, including phosphorylation, O-GlcNAc glycosylation, acetylation, oxidation, and methylation, which influence its binding affinity for tubulin. Among these, phosphorylation is the most extensively studied modification. Tau protein contains numerous potential phosphorylation sites, and its microtubule-binding region, typically positively charged, becomes hyperphosphorylated, losing its positive charge. This leads to the detachment from microtubules, disintegration of the microtubule structure, and subsequent tau aggregation, resulting in NFT formation. These tangles are toxic to neurons and drive neurodegeneration. In vivo and in vitro studies have confirmed that abnormal tau phosphorylation is a critical factor in AD pathogenesis and progression, primarily due to the imbalance in kinase and phosphatase activity, particularly involving GSK-3β and PP2A. GSK-3β, a proline-directed Ser/Thr kinase, is notably hyperactive in AD brains and phosphorylates multiple tau sites (e.g., Ser404, Ser396, Ser199, and Ser202), generating pathological p-tau [116]. Lithium, a GSK-3β inhibitor, indirectly regulates GSK-3β via AKT activation, reducing tau hyperphosphorylation. However, clinical trials with lithium have not demonstrated cognitive improvements or significant effects on cerebrospinal fluid tau biomarkers [117]. A novel GSK-3α/β inhibitor identified in a tauopathy cell model has shown promising results, crossing the blood-brain barrier, ameliorating tau pathology, and reducing tau-related neurotoxicity [118]. PP2A, the most active tau phosphatase in the brain, accounts for approximately 70% of tau dephosphorylation. It restores tau function by counteracting hyperphosphorylation. However, PP2A activity is significantly reduced in AD brains, and its therapeutic targeting remains challenging. Sodium selenate, a known PP2A activator, reduces NFTs in tauopathy models and enhances PP2A activity. Despite these findings, phase 2A clinical trials showed no cognitive improvement, highlighting the need for further clinical validation [119], [120]. Both GSK-3β inhibitors and PP2A activators face challenges related to blood-brain barrier permeability and safety, impacting their clinical development.

Natural products are invaluable resources for drug discovery. Several natural compounds with diverse structures and physiological activities have shown potential in mitigating tau hyperphosphorylation. Flavonoids such as icariin, nobiletin, and kaempferol regulate the PI3K/AKT/GSK-3β pathway, reducing Aβ and tau protein deposition [48], [67], [69], [74]. Compounds like quercetin, baicalin, and G. biloba extract (EGb761) inhibit tau phosphorylation at multiple sites and modulate CDK5 and GSK-3β activities while enhancing PP2A activity [68], [70], [71], [75]. Alkaloids, including evodiamine and berberine, reduce tau phosphorylation and activate PP2A via related signaling pathways [76], [77]. Saponins, such as ginsenosides Rg1, Rg2, Rb1, and Rd, modulate multiple pathways (e.g., PI3K/AKT, ERK/MAPK, and NF-κB) to reduce tau pathology and regulate kinase-phosphatase balance [83], [86]. Polysaccharides from sources like S. chinensis and A. membranaceus also reduce p-tau levels and modulate related kinases [90], [95]. Polyphenols, including curcumin and stilbene glucoside, exhibit antioxidant and anti-inflammatory effects, regulate the PI3K/AKT pathway, and enhance PP2A activity [97], [99]. Other compounds, such as gastrodin, SCH, and OST, target the ERK1/2 and p38 MAPK pathways to reduce tau hyperphosphorylation [100], [103], [105]. Iridoid glycosides, including those from C. officinalis, enhance PP2A activity and modulate tau phosphorylation [109].

Despite their promise, natural products face challenges such as limited bioavailability and blood-brain barrier permeability. Advances in artificial intelligence-driven virtual screening and experimental validation offer efficient approaches for discovering and optimizing natural compounds [121]. Future strategies should focus on kinase-phosphatase balance and the unique structural properties of natural compounds to accelerate drug development. In conclusion, natural products provide a vast reservoir of bioactive compounds with significant potential to regulate tau protein phosphorylation and mitigate AD pathology. These compounds, encompassing diverse structural classes such as flavonoids, alkaloids, saponins, polysaccharides, phenols, and terpenoids, exhibit multicomponent and multitarget effects. By modulating key kinases and phosphatases, such as GSK-3β and PP2A, and interacting with related signaling pathways, these compounds effectively reduce tau hyperphosphorylation, oxidative stress, and inflammation while improving cognitive functions. Despite challenges related to bioavailability and blood-brain barrier permeability, advancements in drug discovery technologies, including AI and experimental validation, hold promise for overcoming these limitations [122], [123]. Moving forward, a deeper understanding of tau pathology and its interaction with natural products will guide the optimization and development of innovative, effective, and safe therapeutic strategies for AD.

In summary, a variety of plant extracts and phytochemicals have demonstrated potential in alleviating tau protein phosphorylation, a critical pathological process in the development of AD. While the compounds discussed in this review exhibit a degree of representativeness, it is important to recognize that natural medicines constitute a vast repository of potential therapeutic agents, and numerous natural compounds remain to be explored and characterized through further research. The studies presented herein provide a basis for additional investigations into the efficacy and mechanisms of action of plant-derived compounds in modulating tau phosphorylation. Future research should focus on elucidating the specific molecular targets and signaling pathways through which these phytochemicals exert their effects. Moreover, identifying structure-activity relationships and optimizing lead compounds may facilitate the development of more potent and selective tau-targeting therapeutics. Translating these findings into clinical applications will necessitate rigorous evaluation of the pharmacokinetic properties, bioavailability, and safety profiles of the most promising candidates. The potential for drug-drug interactions and adverse effects must be thoroughly assessed to ensure the development of safe and effective interventions for AD.

Contributorsʼ Statement

Drafting the manuscript: Z. Chen, Y. Lu, and Y. Wang; conceptualization: J. Liu, L. Yu, and Q. Wang; critical revision of the manuscript: L. Yu and J. Liu.

Conflict of Interest

The authors declare that they have no conflict of interest.

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