With the rapid advancement of modern medicine alongside progress in science and technology, the average life expectancy has significantly increased.¹ This increase in life expectancy signifies a growing elderly population, which in turn has led to a sharp rise in the prevalence of age-related diseases.² According to a report by Alzheimer's Research UK (2023), 49% of UK adults mentioned that dementia is the disease they fear the most. This fear stems from the fact that it not only erases one's sense of identity but also places a considerable burden on families.³ Globally, one person is diagnosed with dementia every three seconds.⁴ In 2020, over 55 million people worldwide were living with dementia, and this number is expected to increase to 78 million by 2030 and 139 million by 2050.⁵

Dementia is a clinical syndrome characterized by a progressive decline in cognitive function, including memory, language, and problem-solving abilities, severe enough to interfere with daily life.⁶ Unlike normal forgetfulness, individuals with dementia fail to retrieve lost information despite prompts or context, and such memory deficits typically worsen over time.⁷ Other symptoms include anomia (difficulty recalling names), and impaired spatial orientation, calculation difficulties, and changes in personality or mood, including depression and sleep disturbance.⁸ The most common disease that can lead to such a state of dementia is Alzheimer's disease (AD).⁹

AD was first identified by Dr. Alois Alzheimer in 1906 in a patient exhibiting progressive cognitive impairment, hallucinations, delusions, and loss of daily living abilities, and the disease was later named in his honor.¹⁰ Despite extensive research on AD, the precise etiology of AD remains unclear.¹¹ However, three key pathological hallmarks have been well-established: senile plaques, neurofibrillary tangles (NFTs), and progressive neuronal loss (Fig. 1).¹² Senile plaques are extracellular deposits primarily composed of beta-amyloid (Aβ) peptides, surrounded by dystrophic neurites and activated microglia.¹³ Aβ is a fragment derived from amyloid precursor protein (APP) via sequential cleavage by β-secretase and γ-secretase.¹⁴ These fragments aggregate into oligomers and fibrils, ultimately forming senile plaques that contribute to synaptic dysfunction and neurotoxicity through mechanisms involving inflammation and oxidative stress.¹⁵

Fig. 1. 
The pathologic characteristics of AD. Senile plaques are mainly composed of Aβ, and neurofibrillary tangles aggregated with hyperphosphorylated tau proteins are hallmarks of AD.

Another key pathological feature of AD is the formation of NFTs.¹⁶ Tau is a microtubule-associated protein that stabilizes microtubule structures in neurons; its biological activity is tightly regulated by phosphorylation.¹⁷ In AD, tau undergoes abnormal hyperphosphorylation, leading to microtubule destabilization.¹⁸ These hyperphosphorylated tau proteins self-assemble into oligomers, sequesters normal tau, and form insoluble filaments that develop into NFTs.¹⁹ The presence and distribution of NFTs in the brain are closely associated with the progression of AD.²⁰ Notably, injection of hyperphosphorylated tau isolated from AD brains into hippocampus of transgenic mice exacerbates tau pathology, supporting its pathogenic role (Fig. 2).

Fig. 2. 
Tau hyperphosphorylation and neurofibrillary tangles. The hyperphosphorylated tau proteins detach from microtubules and aggregate themselves; it eventually leads to the formation of neurofibrillary tangles (NFTs).

Under physiological conditions, tau is phosphorylated at low levels. However, in AD, the level of phosphorylated tau is three- to four-fold higher than in healthy brains.²¹ Key phosphorylation sites involved in AD pathology include Ser199/Ser202/Thr505, Thr212, Thr231/Ser235, Ser262/Ser356 and Ser422 (Fig. 3).²²

Fig. 3. 
Schematic representation of the distribution of tau phosphorylation sites on the longest tau isoform (441 amino acids); The total of 45 sites (depicted in red) are the phosphorylated residues on tau from Alzheimer brain. The residues in the amino-terminal inserts (N1, N2) and the microtubule-binding domain repeat region (R1–R4) are also phosphorylated in the Alzheimer brain, which are not detected in normal physiological condition in adult brains.

Several kinases are implicated in tau hyperphosphorylation, including cyclin-dependent protein kinase 5 (CDK5), glycogen-synthase kinase-3β (GSK-3β), and Mitogen-activated protein kinases (MAPKs).²³ Conversely, protein phosphatases-2A (PP2A) is a critical enzyme that dephosphorylates tau and restores its normal function.²⁴ In AD brains, CDK5 is hyperactivated, while PP2A activity and expression are significantly reduced.²⁵ CDK5 activation, particularly through its truncated activator p25 (a cleavage product of p35), promotes neuronal loss, caspase-3 activation and NFT formation.²⁷ GSK-3β is also a central player in AD pathology; its overactivation disrupts synaptic plasticity,²⁸ impairs spatial memory and triggers neuroinflammation²⁹ Pharmacological inhibition of GSK-3β has been shown to reduces tau hyperphosphorylation, improve behavioral deficits, and decrease Aβ production by downregulating β-secretase activity.³⁰

MAPKs are signaling molecules involved in a wide range of cellular functions including metabolism, proliferation, differentiation, and apoptosis.³¹ In the context of AD, MAPKs are upregulated and contribute to tau hyperphosphorylation.³² Co-precipitation of MAPK with paired helical filament (PHF)-tau further supports its role in AD pathology.³³

Natural products have been used to treat various diseases, for centuries, long before the advent of modern pharmaceuticals.³⁴ The fact that many of the drugs currently in use are either composed of compounds isolated from natural sources or are derived from natural products highlights the importance of natural products in drug development.³⁵ Despite extensive efforts by pharmaceutical companies to develop effective AD therapies, no drugs has yet proven successful in halting or reversing disease progression.³⁶ One key challenge is that AD is multifactorial disease, yet many drug development strategies have targeted only a single pathological mechanism. In contrast, natural products often contain diverse array of bioactive compounds capable of modulating multiple targets simultaneously.³⁷

While numerous reviews have focused on natural products that inhibit Aβ pathology, comparatively fewer have explored compounds that target tau hyperphosphorylationan equally important contributor to AD pathology.³⁸ Therefore, this review aims to highlight natural product-derived components, particularly flavonoids, that modulate tau phosphorylation and offer therapeutic potential for AD.

Flavonoids are a class of naturally occurring polyphenolic compounds widely distributed in various plant species.³⁹ Accumulating evidence suggests that flavonoids possess significant neuroprotective potential, particularly in the context of age-related neurodegenerative disorders.⁴⁰ Among their diverse biological activities, the suppression of tau hyperphosphorylation has drawn increasing attention as a potential therapeutic strategy for AD.⁴¹ This section highlights several representative flavonoids that have demonstrated efficacy in regulating tau phosphorylation, along with their proposed mechanisms of action.

Baicalein (Fig. 4A) is a flavone-type flavonoid predominantly isolated from Scutellaria baicalensis Georgi. (Lamiaceae).⁴² The ethanol extract of S. baicalensis has been reported to exert neuroprotective effects in a spinal cord injury model in rats, primarily by alleviating inflammation and oxidative stress.⁴³ In addition, the total flavonoids extracted from this plant improved memory impairment and mitigated neuronal damage induced by cerebral ischemia.⁴⁴

Fig. 4. 
Structures of wogonin, baicalein, daidzein and morin. (A) Baicalein, (B) wogonin, (C) daidzein, (D) puerarin and (E) morin.

Among the major flavonoids in S. baicalensis, baicalein has been shown to inhibit tau aggregation and promote the dissociation of PHFs in an in vitro study.⁴⁵ In an in vivo study using APP/PS1 transgenic mice, which harbor a chimeric mouse/human APP gene with the Swedish mutation and a Presenilin-1 gene lacking exon 9, oral administration of baicalein at doses of 40 or 80 mg/kg/day for two months significantly reduced tau hyperphosphorylation.⁴⁶ This effect was associated with the inhibition of GSK-3β activity and a reduction in phosphorylated tau at Ser202/Thr205 in the hippocampus, suggesting that baicalein may exert its anti-tau effects through modulation of GSK-3β-mediated signaling pathways. These findings support the potential of baicalein as a promising therapeutic agent targeting tau pathology in AD.

Wogonin (Fig. 4B), another flavone-type flavonoid present in S. baicalensis has also demonstrated activity against tau hyperphosphorylation.⁴⁷ In an in vitro study, wogonin treatment (1–50 μM) of SH-SY5Y neuroblastoma cells and primary neural astrocytes led to a dose-dependent reduction in tau phosphorylation, which was attributed to the inhibition of GSK-3β activation via the mammalian target of rapamycin (mTOR)-mediated signaling.⁴⁸ Furthermore, wogonin administered to triple transgenic AD mice (3xTg-AD) significantly improved spatial memory performance in behavioral tests, including the Morris water maze and Y-maze, while concurrently attenuating both amyloidogensis and tau pathology.⁴⁹ These behavioral improvements were accompanied by biochemical evidence of reduced phosphorylation at key tau sites in the cortex and hippocampus.

In another study, total flavonoids derived from the stems and leaves of S. baicalensis, including wogonin, were administered intraperitoneally at a dose of 100 mg/kg for 60 days in rats with chronic cerebral ischemia. This treatment resulted in a marked decrease in tau phosphorylation in both the cortex and hippocampus, along with reduced activity of GSK-3β and CDK5.⁵⁰ While these findings suggest that wogonin may contribute significantly to the observed effects, further studies using purified wogonin in animal models are warranted to confirm its independent efficacy and clarify its mechanism of action in vivo.

Daidzein (Fig. 4C) is a glycosylated isoflavone-type flavonoid isolated from Pueraria lobata (Wild.) Ohwi (Fabaceae).⁵¹ The neuroprotective effects of P. lobata have been largely attributed to its active compounds, including daidzein and puerarin.⁵²

Daidzein has been shown to attenuate endoplasmic reticulum (ER) stress-mediated neurotoxicity and DNA damage in SH-SY5Y cells by reducing tau hyperphosphorylation through the inhibition of GSK-3β.⁵³ In addition, daidzein was reported to activate AMP-activated protein kinase (AMPK), thereby mitigating homocysteine-induced neurotoxicity in SH-SY5Y cells,⁵⁴ suggesting multiple neuroprotective mechanisms. However, the effects of daidzein on tau pathology have not yet been confirmed in animal models of AD, highlighting the need for further in vivo studies to evaluate its therapeutic relevance.

By contrast, puerarin (Fig. 4D) has received greater attention due to its promising neuroprotective properties. For instance, puerarin was shown to attenuate Aβ-induced neurotoxicity in SH-SY5Y cells, accompanied by a reduction in tau hyperphosphorylation mediated through the suppression of GSK-3β and activation of Wnt β-catenin signaling.⁵⁵ In animal models, puerarin significantly improved cognitive performance in Aβ-treated mice, restored levels of brain-derived neurotrophic factor (BDNF), and decreased the phosphorylation of tau protein in parallel with reduced GSK-3β activity.⁵⁶ Moreover, puerarin administration in APP/PS1 transgenic mice not only improved memory impairment but also significantly reduced Aβ plaque burden and tau hyperphosphorylation in the cortex, in association with GSK-3β inhibition.⁵⁷

Morin (Fig. 4E) is a biflavonoid found in various fruits, particularly isolated from the leaves of Morus alba Linn. (Moraceae).⁵⁸ Extract of M. alba has shown antioxidant and neuroprotective effects, including the alleviation of brain oxidative stress and cognitive impairment in toxin-induced models.⁵⁹

Morin was shown to inhibit tau hyperphosphorylation in Aβ-treated SH-SY5Y cells, although this effect did not appear a direct reduction in reactive oxygen species (ROS), suggesting a tau-targeted mechanism.⁶⁰ In an in vivo study, morin (10 mg/kg, i.p. for 7 days) attenuated tau pathology in the cortex and amygdala of 3xTg-AD mice.⁶¹ Further, oral administration of morin (20 mg/kg for 14 days) alleviated memory deficits in rats with intrahippocampal Aβ₁₋₄₂ injection, an effect associated with decreased neuroinflammation and oxidative damage.⁶² The anti-tau effect of morin was also validated in the JNPL3 transgenic mouse model expressing P301L mutant human tau, supporting its utility in tauopathy beyond Aβ-driven pathology.⁶³

Citrus fruits contain a wide range of flavonoids,⁶⁴ and several of these compounds have been studied for their neuroprotective effects.⁶⁵ Among them, naringin, hesperidin, eriodictyol, and nobiletin have shown promising activity inhibiting tau pathology.^66–68

Naringin (Fig. 5A), a glycosylated from of naringenin, is a flavanone-type flavonoid abundantly present in the peel of Citrus sinensis (L.) Osbeck (Rutaceae).⁶⁹ Naringin inhibited Aβ-induced tau hyperphosphorylation in PC12 cells at 1 μM, primarily through GSK-3β inhibition.⁷⁰ It also decreased tau accumulation in SK-N-AS cells treated with Aβ.⁷¹ In an in vivo study, naringin alleviated AlCl₃-induced AD-like pathology in rats, including tau hyperphosphorylation,⁷² and reduced brain damage in a hyperglycemia-induced neurodegeneration model by inhibiting astrocyte activation and tau phosphorylation.⁷³ Pharmacokinetic studies demonstrated that oral administration of naringin up to 15 mg/kg was safe, with no observable toxicity during 6-month treatment⁷⁴ suggesting its suitability for further clinical development.

Fig. 5. 
Structures of naringin, hesperidin, eriodictyol and nobiletin. (A) Naringin, (B) hesperidin, (C) eriodictyol, and (D) nobiletin.

Hesperidin (Fig. 5B), a glycosylated form of hesperetin, is another flavanone-type flavonoid primarily found in citrus peels.⁷⁵ Hesperidin inhibited okadaic acid-induced tau hyperphosphorylation in SH-SY5Y cells at 5 µM.⁷⁶ It also reduced Aβ and tau accumulation in SK-N-AS cells exposed to AD-like stress.⁷¹ In rats, hesperidin ameliorated AlCl₃-induced neurodegeneration, including oxidative stress, Aβ accumulation, and tau hyperphosphorylation via downregulation of GSK-3β activity.⁷⁷ Pre-treatment of rats with hesperidin attenuated scopolamine-induced memory impairment and histological changes by reducing hyperphosphorylated tau and glial fibrillary acidic protein, and increasing the expression of synaptophysin.⁷⁸

Eriodictyol (Fig. 5C) is a bitter flavonone found in citrus peels, particularly C. limon Burm. f. (Rutaceae).⁷⁹ In animal models, lemon juice rich in eriodictyol attenuated scopolamine-induced cognitive impairment.⁸⁰ Eriodictyol reduced phosphorylated tau expression in Aβ-treated HT-22 cells and decreased both tau and Aβ accumulation in the cortex and hippocampus of APP/PS1 mice.⁸¹ A molecular docking analysis of 35 flavonoids revealed eriodictyol among the top three candidates for GSK-3β inhibition, though further experimental validation is needed.⁸¹

Nobiletin (Fig. 5D) is a polymethoxylated flavone derived from the peel of C. sinensis and C. tangerina Hort. ex Tanaka (Rutaceae).⁸² The peel of C. tangerina has various physiological activities and is particularly known for its neuroprotective activity related to AD.⁸³ It has been traditionally used in Kampo medicine formulations such as Kososan, where it contributed to the attenuation of aging-related mood disturbances and neuroinflammation in mice, along with decreased tau accumulation.⁸⁴ In senescence-accelerated mouse prone 8 (SAMP8) mice, intraperitoneal administration of nobiletin (10 or 50 mg/kg) for 40 days significantly restored memory function and reduced tau hyperphosphorylation and oxidative stress.⁸⁵ Furthermore, nobiletin not only alleviated AD-like pathological characteristics in in vivo animal studies by attenuating Aβ burden, tau hyperphosphorylation and oxidative stress, but also improved motor and cognitive impairment in Parkinson's disease animal models.⁸⁶

Diosmin (Fig. 6A) is a flavone glycoside of diosmetin, originally isolated from Angelica. gigas Nakai (Umbelliferae)⁸⁷ and is now more commonly produced via the dehydrogenation of hesperidin.⁸⁸ The neuroprotective effects of A. gigas root extract have been demonstrated in in vivo animal models.⁸⁹ In a lipopolysaccharide-induced AD-like mouse model, diosmin improved memory performance by attenuating neuroinflammation.⁹⁰ Furthermore, oral administration of diosmin (1 or 10 mg/kg/day) for 6 months in 3xTg-AD mice significantly reduced phosphorylated tau levels in the hippocampus (CA1 and CA3) and cortex—by 55% and 86%, respectively.⁹⁰ This effect was associated with the suppression of GSK-3α/β activation, suggesting that diosmin reduces tau hyperphosphorylation by directly targeting GSK-3-mediated signaling. In addition, diosmin ameliorated chlorpyrifos-induced brain damage by reducing oxidative stress and neuroinflammation, as well as lowering both phosphorylated tau and Aβ levels.⁹¹

Fig. 6. 
Structures of diosmin, eupatin, apigenin, myrisetin, genistein, and quercetin. (A) Diosmin, (B) eupatin, (C) apigenin, (D) myrisetin, (E) genistein, and (F) quercetin.

Eupatin (Fig. 6B) is a trimethoxyflavonol-type flavonoid found in Artemisia. annua L (Asteraceae).⁹² The extract of A. annua is traditionally used to improve cognitive function and is known to target pathological factors of AD.⁹³ Eupatin was initially characterized as an anti-inflammatory and anti-acetylcholinesterase agents.⁹⁴ Recent studies have shown that eupatin inhibits tau hyperphosphorylation. In Neuro-2a (N2a) cells transfected with the pRK5-EGFP-Tau P301L plasmid which induces tau phosphorylation at multiple sites including Ser262, Ser202/Thr205 and Ser396, treatment with eupatin (2 μM) significantly reduced tau phosphorylation at all sites. This effect was attributed to direct binding of eupatin to the GSK-3β active site, thereby inhibiting its activity.⁹⁵

Apigenin (Fig. 6C) is a flavone-type flavonoid abundant in fruits and vegetables and is isolated from Scutellaria pontica C. Koch (Lamiaceae),⁹⁶ Hyptis fasciculata Benth. (Labiatae),⁹⁷ and Jacaranda mimosaefolia D. Don. (Bignoniaceae).⁹⁸ Although apigenin has long been recognized for its antioxidant and anti-inflammatory properties, its neuroprotective effects have gained attention more recently. Apigenin and naringin isolated from Chrysanthemum morifolium Ramat. (Compositae) alleviated corticosterone-induced depression in mice by reducing neuroinflammation and neuronal apoptosis,⁹⁹ and ameliorated neuroinflammation in Parkinson's disease mice.¹⁰⁰ Apigenin reduced tau hyperphosphorylation at Thr231, Ser262, and Ser396 in the N2a-APPsw cells,¹⁰¹ and mitigated tau toxicity in an in vitro study.¹⁰² In AD rat models, apigenin alleviated neurodegeneration by decreasing tau phosphorylation at Thr205 in the hippocampus and reducing the expression of GSK-3β.¹⁰³

Myricetin (Fig. 6D) is a flavanol-type flavonoid found in multiple plant families including the Myricaceae, Polygonaceae, Primulaceae, Pinaceae, and Anacardiaceae.^104–106 Myricetin inhibited tau aggregation¹⁰⁷, tau phosphorylation and inflammatory cytokine production.¹⁰⁸ In addition, it disrupted tau fibril formation,¹⁰⁹ and suppressed GSK-3β-mediated tau phosphorylation in SH-SY5Y cells.¹¹⁰ In transgenic AD mice, intraperitoneal myricetin (20 mg/kg for 2 weeks) significantly reduced p-tau at Ser396, Ser356, and Thr231 without altering total tau.¹¹¹ Myricetin also alleviated post-ischemic brain damage by reducing Aβ, phosphorylated tau, oxidative stress and inflammation.¹¹² Furthermore, myricetin promoted interaction between tau and autophagy-related protein 5, enhancing p-tau clearance.¹¹³

Genistein (Fig. 6E) is an isoflavone-type flavonoid commonly found in the Fabaceae family. It was first isolated from Genista tinctoria L. (Fabaceae)¹¹⁴ and is also abundant in Glycine max (L.) Merr. (Fabaceae).¹¹⁵ Genistein alleviated ER stress-mediated neurodegeneration in SH-SY5Y cells by upregulating the inactive form of GSK-3β,¹¹⁶ and restored the activity of PP2A.¹¹⁷ Genistein improved cognitive function in AD animal models, with concurrent reduction in tau phosphorylation via calcium/calmodulin dependent protein kinase IV (CaMKIV) modulation.¹¹⁸ Additionally, genistein alleviated synaptotoxicity and reduced GSK-3β activity in Aβ-treated mice, and protected against neurodegeneration in ApoE-knockout and diabetic mouse models.¹¹⁹ Genistein also ameliorated brain damage in the obese diabetic mice by increasing neurotropic factors such as NGF and BDNF, and reducing Aβ deposition and tau hyperphosphorylation.¹²⁰

Quercetin (Fig. 6F) is a flavonol widely distributed in plants including Citrullus colocynthis (L.) Schrad (Cucurbitaceae),¹²¹ Vitis vinifera L. (Vitaceae),¹²² and Ribes nigrum L. (Grossulariaceae).¹²³ Quercetin reduced the hyperphosphorylation of tau protein at Ser396, Ser199, Thr231, and Thr205 in okadaic acid-treated cells via Ca2+-calpain-p25-CDK5,¹²⁴ and PI3k/Akt/GSK-3β pathway.¹²⁵ Its IC₅₀ value for GSK-3β inhibition was reported to be 2 μM.¹²⁶ Quercetin also alleviated tau pathology by reducing HSP 70 expression.¹²⁷ Furthermore, quercetin recovered learning and memory function by reducing Aβ burden, oxidative stress, neuroinflammation and tau hyperphosphorylation.¹²⁸ Moreover, exosomes-loaded quercetin suppressed CDK5-mediated tau hyperphosphorylation and subsequently NFT formation¹²⁹, and its delivery via nanocarriers has shown potential for clinical application.¹³⁰

In conclusion, flavonoids are increasingly regarded as promising candidates for the development of anti-AD agents, owing to their diverse structural characteristics and broad biological activities within the central nervous system. Numerous flavonoids, including baicalein, wogonin, daidzein, morin, diosmin, eupatin, naringin, hesperidin, eriodictyol, and nobiletin, have demonstrated potent inhibitory effects on tau hyperphosphorylation in both in vitro and in vivo models. These compounds exert their neuroprotective effects through various mechanisms, such as inhibition of key tau kinases, activation of phosphatases, and modulation of intracellular signaling pathways. Importantly, many of these flavonoids not only reduced tau hyperphosphorylation and aggregation but also improved cognitive performance, attenuated neuroinflammation, and promoted neuronal survival in preclinical models, without evident toxicity. These findings collectively underscore the therapeutic potential of flavonoids as multi-target agents capable of addressing multiple pathological mechanisms in AD. Nevertheless, despite promising preclinical data, further clinical investigations are required to validate their safety, efficacy, and pharmacokinetics in humans. Continued exploration and development of flavonoid-based compounds may contribute significantly to the future therapeutic strategies for AD.