Research Progress on the Role of Puerarin in the Prevention and Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that affects cognitive abilities in the elderly. Puerarin plays an important role in the prevention and treatment of AD. It exerts potential therapeutic effects in multiple aspects, including regulating the expression of amyloid β-protein (Aβ), inhibiting abnormal phosphorylation of microtubule-associated protein-τ (Tau), scavenging free radicals, resisting oxidation, regulating metal metabolism to maintain cholinergic system stability, improving mitochondrial dysfunction, and resisting inflammation. However, the specific mechanisms by which puerarin protects cortical neurons in the brain are not fully explored. Hypothetical therapeutic pathways still require further scientific verification.

Keywords

alzheimer's disease - puerarin - dementia - cortical neurons

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder closely related to the aging process, characterized by the gradual loss of cognitive function. This disease not only severely impacts the quality of life of elderly individuals but also brings a significant socioeconomic burden.[1] Despite substantial efforts by researchers, the pathogenesis of AD remains unclear. Current medications such as memantine and donepezil have unsatisfactory efficacy.[2] Therefore, in-depth research into the pathological mechanisms and therapeutic strategies of AD, identifying its fundamental causes, and developing effective treatments are key to solving this issue.[3] Presently, there are many challenges in finding new drugs that can effectively alleviate symptoms or prevent disease progression, making this an area of intense focus in the scientific community.

Pueraria, the dried root of the perennial leguminous vine Pueraria lobata (Willd.) Ohwi, is sweet, pungent and cool in nature, and it enters the spleen, stomach, and lung meridians. Pueraria was first recorded in Shennong's Classic of Materia Medica (Shen Nong Ben Cao Jing), which describes its effects: “It is mainly effective for thirst, severe fever of the body, vomiting, various pains, promoting yin energy and removing toxicity.” Pueraria has been found to have heat-clearing, detoxifying, antihypertensive, and antioxidant effects.[4] Research has found that pueraria contains various chemical components, primarily including puerarin, puerarin xyloglucoside, and soybean flavonoids, among others.[5] Among them, puerarin is an isoflavone monomer in pueraria, which has the function of improving blood circulation and protecting brain neurons.[6] Relevant studies suggest that puerarin may inhibit the occurrence and progression of AD.[7] This article aims to review the research progress on the role of puerarin in the prevention and treatment of AD and summarize its therapeutic mechanisms in preventing and treating AD, thus providing a reference for further exploration of puerarin's medicinal value.

Traditional Chinese Medicine's Understanding of Alzheimer's Disease

Traditional Chinese medicine (TCM) believes that the brain marrow plays a crucial role in regulating mental activities in the human body. The Danger Zone of Medicine (Yi Bian) states: “The brain is the sea of marrow, and marrow is derived from essence. When essence is insufficient, it should be replenished with flavors, which all ascend to the brain as the source of generation and transformation.” Zhang et al.[8] believe that brain marrow constitutes the material foundation for mental activities, and therefore, the deprived nourishment to the brain marrow is closely related to the onset of AD. In The Yellow Emperor's Inner Classic: Basic Questions (Huang Di Nei Jing Su Wen), it is stated: “At the age of forty, half of the yin qi in their body has already been consumed, early aging begins to appear in their daily activities; at the age of fifty, their body becomes heavy and their eyes and ears cannot see and hear well…” This describes the phenomenon of physical decline with age. Among the many influencing factors of AD, age is critically important, suggesting that aging is a key factor in the development of AD. Additionally, in Benshen: Basic State of Spirit (Ling Shu:Ben Shen), it states: “The kidney stores essence and essence houses understanding ability”; In The Yellow Emperor's Inner Classic: Basic Questions (Huang Di Nei Jing Su Wen), it states: “The kidney is the organ similar to an official with great power and is responsible for further digestion of skills,” which emphasizes the close connection between the kidney and brain function such as memory and intelligence.[9] In The Yellow Emperor's Inner Classic: Basic Questions (Huang Di Nei Jing Su Wen), it states: “If the kidney fails to produce marrow, bone marrow will become deficient.” This highlights the relationship between kidney qi and brain marrow, with the fundamental pathology of dementia mainly involving the depletion of kidney essence and the deficiency of brain marrow. Modern research further reveals that puerarin can stabilize cerebral vascular function, improve blood circulation in the brain, enhance oxygen and blood supply to the brain, and protect nerve cells in the central nervous system. Therefore, puerarin demonstrates significant medicinal potential in combating AD.

Mechanism of Puerarin in Alzheimer's Disease

The pathogenesis of AD is extremely complex, and a specific cause has not yet been discovered. However, several theories have partially explained the mechanisms underlying AD, mainly involving the related mechanisms of deposition of amyloid β-protein (Aβ), hyperphosphorylation of microtubule-associated protein-τ (Tau), metal ion imbalance, cholinergic system disorder, mitochondrial dysfunction, and neuroinflammation[10] (see [Fig. 1]).

Fig. 1 Mechanism of Alzheimer's disease (AD). ACh, acetylcholine; AChE, acetylcholinesterase; BChE, butyrylcholinesterase; ChAT, choline acetyltransferase; ROS, reactive oxygen species.

Puerarin Reduces the Expression of Amyloid β-Protein in Alzheimer's Disease

Aβ is a protein fragment generated by the cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The deposition of Aβ is considered a hallmark of AD.[11] Aβ may exacerbate the progression of AD through various pathways, including activating glial cells to induce inflammation, increase oxidative stress, damage mitochondrial function, and activate specific signaling pathways that lead to abnormal phosphorylation of Tau protein.[12] Studies have shown that puerarin significantly reduces the levels of Aβ_40/42 in SH-SY5Y cells, demonstrating its significant role in maintaining the function of brain neurons.[13] Other studies have found that puerarin can reduce β-secretase activity and the mRNA level of β-secretase,[14] thereby reducing the expression of Aβ. Puerarin can also inhibit apoptosis of PC12 cells induced by Aβ_25–35, further confirming its protective effect on nerve cells.[15] In AD rat brain tissue, puerarin intervention led to a decrease in the expression of Aβ_1–40 and Bax,[16] as well as reduced levels of propylene glycol content and lactate dehydrogenase leakage, while superoxide dismutase (SOD) levels increased. Estrogen response element (ERE) reporter gene analysis showed that puerarin could preferentially upregulate androgen receptor expression without upregulating estrogen receptor expression, thus promoting Aβ degradation and enhancing neuroprotection.[17] These findings suggest that puerarin can treat AD by regulating Aβ expression. Puerarin regulates the phosphorylation level dependent on vascular growth factors by reducing the expression of protein kinase B and endothelial nitric oxide synthase, thereby improving Aβ₄₀-induced human endothelial cell function.[18]

Puerarin Inhibits the Hyperphosphorylation of Tau Protein

The phosphorylation state and the tertiary structure of Tau protein lead to an increase in its phosphorylation pattern. When Tau protein undergoes pathological hyperphosphorylation, it tends to aggregate into paired helical filaments, eventually leading to neurofibrillary tangles (NFTs), which is one of the main pathological features of AD.[19] Experiments have shown that puerarin can enhance memory function in rats, reduce Aβ levels, and inhibit the phosphorylation process of Tau protein.[20] Glycogen synthase kinase 3β (GSK-3β), a highly conserved serine/threonine kinase, plays a crucial role in the connection between Aβ and NFTs.[21] Puerarin can also activate the GSK-3β-Ser9 and Wnt/β-catenin signaling pathways, increasing β-catenin and Cyclin D1 expression in the G₁/S phase.[22] It can also regulate the level of FGF-2 to inhibit the overactivation of GSK-3,[23] thus alleviating Tau hyperphosphorylation and inhibiting Aβ-induced Tau hyperphosphorylation. Research by Yu et al.[24] found that puerarin regulates the level of Tau protein phosphorylation in AD model rats, and its mechanism is closely related to GSK-3β activity. Another study found that puerarin significantly reduces the phosphorylation level of Tau protein at the Ser199/202 site in the hippocampus of aged rats.[25] Furthermore, puerarin can inhibit Aβ-induced Tau protein phosphorylation at Ser396 and Thr231 in SH-SY5Y cells, as well as increase the number of Pser404 tau-positive cells in the rat hippocampus induced by Aβ, thereby alleviating Tau hyperphosphorylation. Other research indicates that various physiological stresses produced during exercise can enhance the expression of small molecular weight heat shock protein B5 (HSPB5), which increases the structural stability of Tau monomers and inhibits the aggregation of Tau monomers.[26]

The Effect of Puerarin on the Scavenging of Oxygen Free Radicals and Antioxidant Activity

Reactive oxygen species (ROS) are widely present in nature, and the generation and elimination of free radicals in the body generally maintain a dynamic balance, which is crucial for normal physiological functions.[27] Excessive oxidative stress in the brain leads to the generation of Aβ, and the imbalance between the production and elimination of oxygen free radicals can cause abnormal autophagy in hippocampal neurons, thereby exacerbating AD.[28] Puerarin can scavenge oxygen free radicals, inhibit erythrocyte hemolysis and lipid peroxidation processes, demonstrating its antioxidant properties and its ability to prevent free radical damage. Studies have shown that puerarin can reduce the levels of malondialdehyde (MDA) in the prefrontal cortex region and increase the activity of SOD.[29] Additionally, puerarin treatment in AD mice also elevated the activity of glutathione peroxidase (GPx),[30] effectively alleviating brain tissue damage caused by oxidative stress. Oral administration of puerarin can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) target gene heme oxygenase-1 in the hippocampus to reduce oxidative stress.[31] After puerarin treatment, the activities of GPx and SOD in the substantia nigra of injured rats increased, and MDA levels decreased, thereby enhancing antioxidant capacity.[32] Studies have shown that puerarin can reduce the accumulation of ROS in cells and, by regulating the Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio, block the activation of c-Jun N-terminal kinase (JNK), P38 protein, and caspase-3, it inhibits cell apoptosis caused by oxidative stress.[33] MicroRNAs (miRNAs) have predictive value for the pathogenesis of AD.[34] Some miRNAs may participate in the occurrence of oxidative stress through pathways such as mitogen-activated protein kinase (MAPK), neurotrophic factor signal transduction, axonal guidance, hormone synthesis, and insulin signal transduction.[35] Puerarin can regulate miR-214 in neural stem cells to mitigate hypoxia-induced damage.[36]

The Role of Puerarin in Regulating Metal Ion Metabolism Disorders

The imbalance of metal ions is closely related to the occurrence and development of AD. Studies have found that metal ions can participate in various mechanisms, such as Aβ deposition, NFTs, oxidative stress, and neuroinflammation, thereby contributing to the pathogenesis of AD.[37] The imbalance of intracellular iron homeostasis can lead to the generation of excessive ROS through the Fenton reaction, which causes severe damage to cells and results in ferroptosis, a form of iron-dependent cell death.[38] The end product of ferroptosis, 4-hydroxy-2,3-trans-nonenal (4-HNE), promotes the formation of Aβ fibrils and NFTs in AD, thereby exacerbating the inflammatory response.[39] In APP/PS1 mice treated with puerarin, the levels of iron and MDA significantly decreased, while the activities of SOD and GPx increased, and the levels of interleukin (IL)-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) significantly decreased.[37] Puerarin also promoted the action of relevant lipolysis carriers and GPx 4, and inhibited the expression of long-chain acyl-CoA synthetase 4 and lysophosphatidylcholine acyltransferase 3.[40] Additionally, puerarin downregulated the expression of divalent metal ion transporter 1 (DMT1) in the cerebral cortex of AD mice and upregulated the expression of ferroportin 1 (FPN1),[41] thereby alleviating neurodegeneration caused by iron overload and reducing endothelial cell damage caused by iron overload.[42] These results indicate that puerarin can inhibit ferroptosis and oxidative stress to improve cognitive function in AD. Aluminum has been confirmed to have certain neurotoxic effects in AD.[43] Experiments have shown that puerarin can regulate neurotransmitter homeostasis and concentration levels, as well as increase the concentrations of metal ions such as iron, magnesium, and zinc, thereby achieving metal ion homeostasis and normal function of the central nervous system.[44] At the same time, puerarin also significantly improves damage to the brain tissue and serum antioxidant systems in aluminum-poisoned rats.[45] Aβ can disrupt calcium ion homeostasis, which in turn affects signaling pathways in various mechanisms, and exacerbates cognitive dysfunction.[46] Puerarin can maintain calcium ion concentration homeostasis while upregulating brain-derived neurotrophic factors, thus protecting hippocampal neurons in rats and alleviating neuronal damage caused by calcium overload.[47] In addition to regulating calcium ion concentrations, puerarin can influence calcium ion dependence and the activity of calcium ion channels by enhancing calcium release,[48] and it can reduce the activity of calmodulin-dependent protein kinase II, thereby inhibiting calcium ion influx and providing neuroprotective effects.[49]

Puerarin Maintains the Stability of the Cholinergic System

Cholinergic signaling is crucial for memory formation, learning processes, attention, and higher cognitive functions. Defects in the cholinergic system can impair the learning and memory abilities of AD patients, thereby exacerbating disease progression.[50] Several studies have shown that puerarin can enhance learning and memory abilities in mice by increasing the levels of choline acetyltransferase (ChAT) and acetylcholine (ACh), and by reducing the activity of acetylcholinesterase (AChE).[51] Research also suggests that puerarin can improve nerve damage by reducing the activity of butyrylcholinesterase (BChE).[52] Additionally, puerarin can regulate the levels of the monoamine neurotransmitter serotonin, thereby restoring normal hippocampal function.[53] Some other studies indicate that puerarin can reduce the activity of dopamine and norepinephrine, among other monoamine neurotransmitters, in animal models induced by actinomycin,[54] and also lower the levels of 5-hydroxyindoleacetic acid in the rat brain,[55] thereby maintaining the normal operation of the cholinergic system. Research by Mei and others[56] found that puerarin activates the cholinergic anti-inflammatory pathway (CAP), inhibits proinflammatory factors, enhances immune cell activity, promotes the production of the anti-inflammatory cytokine IL-10, and thus regulates immune responses and inflammation.

Puerarin Improves Mitochondrial Dysfunction

Mitochondria, as important dynamic organelles within cells, primarily meet the majority of cellular adenine nucleoside triphosphate (ATP) demands through oxidative phosphorylation.[57] Mitochondrial dysfunction is closely related to aging and neurodegenerative diseases, with mitochondrial dysfunction being particularly prominent in the early stages of AD.[58] Puerarin helps maintain the integrity and clarity of the mitochondrial structure in rat neural cells, suggesting that it may protect neurons by maintaining mitochondrial homeostasis and preventing apoptosis.[59] Mitochondrial autophagy involves kinase protein 1 (Pink1) and E3 ubiquitin ligase (Parkin), with the Pink1/Parkin pathway widely recognized as the main mechanism for clearing damaged mitochondria.[60] Puerarin can block PINK1–Parkin and Nix-mediated mitochondrial autophagy, inhibit Cd-induced reduction of mitochondria in rat cortical neurons,[61] increase the protein expression levels of mitochondrial PINK1, Parkin, and Nix-like protein X,[62] and reduce the expression of proteins associated with the mitochondrial unfolded protein response following external stimuli.[63] Puerarin exerts a neuroprotective effect by inhibiting the release of mitochondrial cytochrome C and thereby reducing apoptosis.[64] Puerarin can also reduce cytoplasmic hybrid cell apoptosis and lower ROS levels to restore mitochondrial function, thus protecting sporadic alzheimer's disease (SAD), which is closely related to oxidative stress. Additionally, evaluating ATP content and determining the ratio of nicotinamide adenine dinucleotide (NAD⁺/NADH) has shown that puerarin can alleviate mitochondrial damage in the rat cerebral cortex,[65] improve mitochondrial function, and reduce oxidative damage in endothelial cells.[66]

The Anti-inflammatory Effects of Puerarin

Neuroinflammation is primarily initiated by immune responses triggered by the activation of microglia and astrocytes in the central nervous system.[67] Neuroinflammation contributes to Aβ deposition, neuronal damage, and NFTs, creating a vicious cycle that exacerbates AD.[68] Puerarin can reduce the activation of microglia, decrease the release of proinflammatory factors, and improve the learning and memory abilities of mice.[69] Puerarin can influence the activation of protein kinase C δ (PKC-δ), IκB kinase β (IKKβ) and nuclear factor kappa-B (NF-κB) pathways by inhibiting caspase-8 activation, which reduces caspase-3 activity,[70] [71] and decreases the levels of inflammatory factors such as nitric oxide, TNF-α, and IL-1β, thereby alleviating inflammation. Puerarin activates intracellular phosphatidylinositol kinase and Ras/MAPK signaling pathways, increases the expression of phosphorylated extracellular-regulated protein kinases and brain-derived neurotrophic factors, activates protein kinase B and Bcl-2 genes to reduce astrocyte apoptosis,[72] and inhibits the expression of astrocytes to exert anti-inflammatory effects. Research by Dong et al.[73] found that puerarin can reduce swelling in astrocytes and the expression of lactate dehydrogenase. Additionally, puerarin can protect the brain by inhibiting the inflammation-related NOD-like receptor thermal protein domain associated protein 3/cysteinyl aspartate specific proteinase-1/Gasdermin D (NLRP3/Caspase-1/GSDMD)-mediated pyroptosis pathway and reducing blood–brain barrier damage.[74] Puerarin can also improve changes in inflammatory factors such as TNF-α, interferon-γ (IFN-γ), transforming growth factor-β1 (TGF-β1), and IL-1β in mouse serum, reducing the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) proteins, thus alleviating endothelial cell damage.[75]

Other Effects

Puerarin can also promote the recovery of rat neural function by repairing synaptic structures and enhancing synaptic transmission function.[76] It can reduce neuronal apoptosis by downregulating the proapoptotic gene Bax, upregulating the antiapoptotic gene Bcl-2, and inhibiting the expression of Caspase-3.[77] Puerarin improves the fluidity of neuronal cell membrane lipids and protects neural cells. Experimental studies have shown that puerarin pretreatment can prevent ischemia–reperfusion injury in brain tissue by alleviating microvascular damage, increasing recanalization, reducing blood–brain barrier permeability and alleviating brain edema, and it also protects vascular endothelial cells and reduces endothelial cell dysfunction under pathological conditions.[78]

Conclusion

In summary, puerarin has shown potential therapeutic effects for AD in various aspects, including regulating Aβ expression, inhibiting abnormal phosphorylation of Tau proteins, scavenging oxygen free radicals, resisting oxidation activity, regulating metal metabolism, and eliminating inflammation.[79] Given the highly complex pathological mechanisms of AD, puerarin, as one of the main active ingredients in pueraria, still has many unresolved mysteries in its pharmacological effects. The specific mechanisms by which puerarin protects cortical neurons in the brain are not yet fully understood. Some hypothetical therapeutic pathways require further scientific verification to be confirmed. Therefore, to comprehensively reveal the practical effects of puerarin in the prevention and treatment of AD and the underlying mechanisms, there is an urgent need for more systematic clinical trials and basic research. This is of great significance for establishing puerarin's important position in future prevention and treatment strategies for AD.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Changsong Chu: Project administration and validation. Yaquan Jia: Conceptualization, data curation, and writing—original draft. Yuan Liu: Data curation, methodology, and writing—review and editing. Ruofei Du: Data curation and software. Zichuang Wang: Methodology and writing—review and editing. Zhenqiang Zhang: Formal analysis and investigation. Wanchun Zheng: validation. Junying Song: Data curation.

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Publication History

Received: 08 November 2024

Accepted: 12 January 2025

Article published online:
08 April 2025