Neurodegenerative diseases are suffering from many people, and among them, Alzheimer’s disease affects people all over the world. Dementia is a disease that causes impairments in daily living skills such as memory, language, and other cognitive abilities. Currently, approximately 55 million people worldwide suffer from Alzheimer’s disease. It is a progressive disease, and it is expected that in the United States, approximately 6.7 million people aged 65 and older will have Alzheimer’s dementia by 2023, 73% of whom will be aged 75 and older ^(1,2).

The mechanism by which Alzheimer’s disease develops is still unclear. But recent evidence is increasingly suggesting that variety interactions between environmental and genetic factors may influence Alzheimer’s disease ⁽³⁾. As Alzheimer’s disease progresses, amyloid beta (Aβ) accumulates in the brain’s medial temporal lobe and cortical structures, causing neuroinflammation and neurofibrillary tangles (NFTs). Dr. Alois Alzheimer, a German psychiatrist, described Alzheimer’s disease as a severe brain disorder characterized by widespread neuronal death and the accumulation of amyloid plaques while examining the brain of the first patient who experienced memory loss and personality changes before death. The disease was named Alzheimer’s disease in honor of this doctor ⁽⁴⁾.

Currently, N-methyl D-aspartate (NMDA) antagonists and cholinesterase inhibitors are used to treat Alzheimer’s disease. These drugs can not completely cure Alzheimer’s disease and have been used to alleviate symptoms and slow its progression ⁽⁴⁾. Recently, researchers are interested in developing therapeutics using natural products. According to previous Studies, Natural products are valuable for drug development because of their structural complexity and chemical properties. As research progresses, more characteristics and structural features of natural products are being identified, making them an important source of new compounds in drug research and development ⁽⁵⁾.

This paper summarizes the effects of natural products on Alzheimer’s disease. In this paper, we explained the mechanism by which each natural product exhibits effects on Alzheimer’s disease. Through this, we suggest that natural products can not only be used to prevent Alzheimer’s disease but can also be used as effective drugs for treatment.

Alzheimer’s disease is divided into early-onset and late-onset types depending on when the disease occurs. Early-onset Alzheimer’s disease is hereditary and accounts for a minority of all Alzheimer’s disease patients, so most patients suffer from late-onset Alzheimer’s disease. Currently, the pathogenesis of Alzheimer’s disease is unclear. However, there is no doubt that amyloid plaque accumulation, neuroinflammation, and intracellular NFTs due to tau protein are the major pathological markers of the disease ⁽⁶⁾. It is also widely known that Alzheimer’s disease is caused by oxidative stress and mitochondrial dysfunction (Fig. 1).

Fig. 1. Pathophysiology of Alzheimer’s disease. Aβ, amyloid beta.

1. Formation of Aβ in Alzheimer’s disease

Aβ is one of the representative pathological features of Alzheimer’s disease. Amyloid pathogenesis begins when amyloid precursor protein (APP), an essential protein of the cell membrane, is cleaved to form insoluble Aβ fibrils, and beta-secretase and gamma-secretase are involved. There are two main types of Aβ polymers directly involved in plaque formation and neurotoxicity induction: Aβ40 and Aβ42. Aβ42 is less abundant than Aβ40 and highly insoluble, severely neurotoxic, more prone to aggregation, and acts as a toxic component of the Aβ polymer structure ⁽⁷⁾. Evidence is accumulating that Aβ is central to the initiation of Alzheimer’s disease, and a fundamental element of the amyloid hypothesis is that the accumulation of Aβ initiates a cascade of reactions that lead to neurodegeneration. Familial Alzheimer’s disease is strongly associated with Aβ42. Mutations in APP and presenilin increase Aβ42 production and cause familial Alzheimer’s disease with almost 100% penetrance ⁽⁸⁾. When tau protein is absent, Aβ oligomer do not cause fatal neurotoxicity, which suggests that individual Aβ oligomers do not initiate the pathology of Alzheimer’s disease. In summary, the amyloid cascade hypothesis suggests that Aβ aggregation occurs independently of NFTs formation and leads to cellular and molecular events such as microglial and astrocyte activation, neuroinflammatory responses, and oxidative stress.

2. Neuro-inflammation in Alzheimer’s disease

The neuroinflammation hypothesis is suggested that the continuous activation of inflammatory cells is the main cause of Alzheimer’s disease through signaling by microglia in the central nervous system. When microglia fail to regulate the damage to the anti-inflammatory cytokines and lipid genome, they cause more inflammation and increased levels of hyperphosphorylated tau protein by damaging neuronal degeneration and metabolites. Long-term immune response activation worsens Alzheimer’s disease. This process begins to neuronal damage by causing Aβ accumulation and continuous secretion of pro-inflammatory cytokines that being to damage neurons ⁽⁶⁾.

3. Phosphorylation of tau protein in Alzheimer’s disease

In addition to amyloid plaques, another pathological hallmark of Alzheimer’s disease is NFTs, with the major component being tau protein. Tau is one of the microtubule-associated protein families, including various microtubule-binding repeats that stabilize microtubules by binding to tubulin ⁽⁹⁾. Binding activity is regulated by the levels of phosphorylation and dephosphorylation, and multiple kinases and phosphatases are involved in this process. Biochemical characterization of tau phosphorylation shows that it disrupts tau binding to microtubules and alters the charge and structure within the microtubule-binding domain, thereby inducing tau to self-assemble into tangles/filaments. Subsequently, microtubules disintegrate, axonal transport function is impaired, eventually leading to neuron death ^(9,10). The interaction between neuroinflammation and amyloid allows tau proteins to spread, ultimately resulting in widespread brain damage and cognitive impairment ⁽⁶⁾.

4. Oxidative stress in Alzheimer’s disease

The brain consumes about 20% of the body’s total oxygen, making it more susceptible to reactive oxygen species (ROS) and reactive nitrogen species ^(11,12). ROS have a very unstable structure because they have unpaired electrons in their molecules, and they can interact with nerve cells because they contain a lot of polyunsaturated fatty acids (PUFAs). This interaction may lead to lipid oxidation, changes in the redox potential of Aβ metal ions, or mitochondrial dysfunction, which in turn contribute to neuronal cell death. Neuronal cell death is associated with cerebral cortical atrophy and is a contributing factor in Alzheimer’s disease ⁽²⁾. The interaction between glycol-proteins and ROS generates advanced glycoxidation end products, which are highly toxic to neurons. Additionally, these reactions may trigger neuroinflammation in the patient’s brain by releasing inflammatory mediators such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α ⁽¹³⁾.

5. Mitochondrial dysfunction in Alzheimer’s disease

Mitochondria are essential cellular organelles that produce ATP, the energy required for cells, and maintain the biological functions of cells. Mitochondria are usually equipped with an antioxidant system including cytochrome C oxidase ⁽¹⁴⁾, and mitochondrial metabolism has a huge impact on the function of immune cells. One study found that impaired mitophagy led to cognitive impairment by influencing Aβ and tau accumulation through increased oxidative damage and mitochondrial energy defects ⁽¹⁵⁾. In addition, as Alzheimer’s disease progresses, there is a notable reduce activity of hippocampal cytochrome C oxidase, the mechanism that mitochondria’s defense against ROS is impaired ^(14,16,17).

Natural products have been utilized to treat various ailments since ancient times and now play a crucial role in modern pharmaceuticals. This is especially evident in the development of antibiotics and cancer treatments. Significant progress in cancer therapy is closely linked to the discovery of drugs derived from natural sources. Nature offers a vast array of resources due to its ongoing biological activity and diverse chemical properties ⁽¹⁸⁾. Owing to their wide-ranging pharmacological properties, natural products are being explored for their potential use in therapeutic strategies for neurodegenerative diseases ⁽¹⁹⁾. Unlike synthetic drugs, natural compounds can target multiple pathways and do not require complex synthesis processes, providing a significant advantage (Table 1) ⁽⁶⁾.

Table 1

Natural products that alleviate Alzheimer’s disease

Natural product	Composition	Function	Reference
Therapeutic phytochemicals
Red ginseng	Ginsenoside	Regulating neuroinflammatory pathways Reducing inflammatory factors and APP expression Inhibiting the aggregation of Aβ and tau proteins	(22-25)
Ginkgo biloba extract	Flavonoids, terpenoids, organic acids	Regulating the balance of gut microbiota	(26,27)
Green tea (Camellia sinensis)	Tea polyphenols, caffeine, theanine	Penetrating the brain-blood barrier Inhibiting acetylcholinesterase Improving memory and hippocampal long-term potentiation Regulating hippocampal synaptic efficacy through the dopamine D1/5-PKA pathway	(29-31)
Barberries	Berberine	Suppressing the production of IL-6 and MCP-1 Downregulating the expression of COX-2 and NOS Inhibiting the activity of BACE-1	(34-37)
Therapeutic marine chemicals
DHA/EPA (omega-3)	DHA/EPA	Decreasing the levels of arachidonic acid Increasing the levels of several signaling factor related to synaptic function Increasing dendrites and synapses Improving hippocampal neurogenesis	(40,42)
Seaweed	LXR-activating (oxy)phytosterol, PPAR-activating fatty acid	Enhancing cholesterol efflux Transcriptional inhibiting of inflammatory transcription factors	(50-52)
Algae	Polyphenols, polysaccharides, sterols	Inhibiting AChE and BChE, antioxidant activity Protecting the mitochondrial membrane potential Inhibiting α-synuclein and tau protein aggregation Improving the formation of Aβ peptide aggregates	(54,55)
Marine sponges	Pyridoacridine alkaloid	Inhibiting AChE activity	(56-58)

APP, amyloid precursor protein; Aβ, amyloid beta; IL-6, interleukin-6; MCP-1, monocyte chemotactic protein-1; COX-2, cyclooxygenase-2; NOS, nitric oxide synthase; BACE-1, beta-site APP cleaving enzyme-1; LXR, liver X receptor; PPAR, peroxisome proliferator-activated receptor; AChE, acetylcholinesterase; BChE, butyrylcholinesterase.

1. Therapeutic phytochemicals for Alzheimer’s disease

In recent years, increasing interest in the potential of phytochemicals to prevent various neurodegenerative diseases has prompted numerous studies. These studies have shown potential and have captured the attention of scientists, researchers, and the public. Medicines derived from plants have been used steadily in the healthcare systems of underdeveloped countries. Plant-based medicines are economically advantageous compared to synthetic drugs because they have low toxicity and minimal health risks. Herbal medicines are widely used in traditional treatments due to their psychoactive, adaptogenic, and neuroprotective properties for various diseases ⁽²⁰⁾.

1) Red ginseng

Red ginseng, created by steaming and drying fresh ginseng, is widely utilized in traditional oriental medicine. Advances in technology have led to improved processing techniques for red ginseng, resulting in various products such as fresh ginseng, black ginseng, fermented red ginseng, and enzyme-treated red ginseng ⁽²¹⁾. Ginsenosides, the saponins unique to ginseng species, differ from those in other plants. Red ginseng helps reduce neuroinflammation induced by Aβ and mitigates symptoms of neurodegenerative diseases by modulating neuroinflammatory pathways like mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain enhancer of activated B cells. It also decreases inflammatory factors such as TNF-α, IL-1β, cyclooxygenase-2 (COX-2), and nitric oxide ^(22,23). Although the precise mechanism by which red ginseng reduces inflammation is not fully understood, it is known that ginsenoside Rg1 lowers APP expression and Aβ accumulation in mice, thus protecting neurons ⁽²⁴⁾. Red ginseng also aids in the degradation of tau by inhibiting its aggregation and reducing tau phosphorylation in the hippocampus and cerebral cortex ⁽²⁵⁾. Studies have demonstrated that red ginseng can prevent the aggregation of Aβ and tau proteins and alleviate related inflammation, suggesting its potential effectiveness in mitigating Alzheimer’s disease.

2) Ginkgo biloba extract

Recent research indicates that human gut microbiota and its metabolites can influence metabolism and regulate physiological functions associated with neurodegenerative diseases ⁽²⁶⁾. Extracted from the Ginkgo tree, G. biloba contains flavonoids, terpenoids, and organic acids. This extract is known for its various pharmacological effects and is believed to benefit cardiovascular and cerebrovascular health. Consumption of G. biloba extract can enhance local or systemic immune responses by balancing gut microbiota, which may have significant health implications. These interactions suggest that long-term use of G. biloba extract can improve cognitive impairment by promoting the growth of beneficial bacteria and maintaining intestinal homeostasis ⁽²⁷⁾.

3) Green tea (Camellia sinensis)

Tea has a long history, originating in China and spreading around the world. In China, it is divided into green tea, yellow tea, white tea, black tea, dark tea, and oolong tea according to the degree of fermentation. Among these, green tea is the first tea discovered and is unfermented ⁽²⁸⁾. Tea polyphenols, caffeine, and theanine, which are extracted and isolated from green tea, have pharmacological activities including anticancer, antioxidant, and neuroprotective effects. Polyphenols contained in green tea are used in the treatment of neurodegenerative diseases because they have brain penetrability ⁽²⁹⁾. Previous studies have shown that green tea extract can significantly improve learning and memory in aged mice and selectively inhibit acetylcholinesterase (AChE) ⁽³⁰⁾. In another study, L-theanine from green tea was able to improve memory and hippocampal long-term potentiation in Alzheimer’s disease mice. This effect is thought to be associated with the regulation of hippocampal synaptic efficiency via the dopamine D1/5-PKA pathway ⁽³¹⁾. One study showed that green tea has a better neuroprotective effect against memory decline and hippocampal oxidative stress in Alzheimer’s disease mice than black tea ⁽³²⁾.

4) Barberries

Berberine is found in plants such as Berberis vulgaris (Barberry), Berberis aristate (tree turmeric), Berberis thunbergia, Coptis chinensis (Chinese goldthread), Hydrastis canadensis (goldenseal), and Mahonia aquifolium (Oregon grape), mainly in the roots, rhizomes, stems, and bark of these plants. Once used as a yellow dye due to its yellow pigmentation, it has also been used in herbal medicine. Berberine has been shown to enhance the survival, development, and function of neurons while protecting electrically excitable brain cells ⁽³³⁾. In one study, berberine was found to suppress the production of monocyte chemotactic protein-1 and IL-6 stimulated by Aβ and downregulate the expression of COX-2 and inducible nitric oxide synthase by blocking MAPK and phosphoinositide 3-kinase/protein kinase B signaling pathways in primary microglial and BV2 cells ⁽³⁴⁾. Another study found that berberine can reduce the level of Aβ by inhibiting the activity of beta-site APP cleaving enzyme-1 ^(35-37).

2. Therapeutic marine chemicals for Alzheimer’s disease

Recent research has revealed that the marine environment harbors a diverse array of unique compounds with significant biological and pharmacological properties, such as polysaccharides, carotenoids, polyphenols, sterols, and alkaloids ⁽⁶⁾. These marine-derived compounds come from edible natural organisms and are extensively used in food, cosmetics, and various industrial applications, many of which are considered safe for consumption and use ⁽³⁸⁾.

1) DHA/EPA (omega-3)

A PUFA is a type of fatty acid characterized by a hydrocarbon chain containing two or more double bonds. Extensive research has demonstrated their anti-inflammatory properties and potential therapeutic applications in neurodegenerative diseases ⁽³⁹⁾. Studies in both humans and animals consuming diets rich in DHA and EPA have shown an increase in the proportion of PUFAs in the cell membranes of inflammatory cells and a decrease in arachidonic acid levels, which can cause inflammation ⁽⁴⁰⁾. These anti-inflammatory effects can help mitigate neurological and psychological symptoms, stabilize mood, enhance cognitive function, and lower the risk of dementia ⁽⁴¹⁾. Additionally, omega-3 intake has been found to elevate levels of several signaling factors related to synaptic function, which promotes dendrite and synapse formation and improves hippocampal neurogenesis, even in older adults ⁽⁴²⁾. Positive effects have also been observed on language skills and object location memory ⁽⁴³⁾. These benefits of omega-3 appear to be more noticeable in patients with very mild Alzheimer’s disease, indicating that omega-3 may be effective even when brain function impairment is slight ⁽⁴⁴⁾. The excellent sources of EPA and DHA are known to be oily fish, and DHA is also found in egg yolks at about 0.7% ⁽⁴¹⁾.

2) Seaweed

The nuclear liver X receptor (LXRα/β) and peroxisome proliferator-activated receptor (PPAα/γR) are involved in regulating various biological processes such lipid metabolism and inflammation, and their activation has attracted attention as a new therapeutic strategy for neurodegenerative disease because it exhibits neuroprotective effects ^(45-48). One study showed that Sargassum fusiforme had a positive effect on cognitive function and Alzheimer’s pathology in an Alzheimer’s mouse model ⁽⁴⁹⁾. S. fusiforme contains both (oxy)phytosterol and fatty acid that activate LXR and PPAR. LXR activation is believed to prevent Alzheimer’s disease progression by increasing cholesterol outflow through the secretion of lipoprotein-like particles containing apolipoprotein E, which provide cholesterol and other lipids to neurons to support synaptic plasticity and neuronal regeneration after injury. Additionally, activation of LXR and PPAR can alleviate inflammation through transcriptional inhibition of inflammatory transcription factors ^(50-52).

3) Algae

Algae, autotrophic organisms that primarily live in aquatic environments and conduct photosynthesis, are classified into Rhodophyta (red), Chlorophyta (green), and Phaeophyta (brown). They contain proteins, vitamins, minerals, dietary fibers, and important physiologically active compounds such as polyphenols, polysaccharides, and sterols, which confer various nutritional and medicinal properties, including antioxidant, anti-inflammatory, and anticancer effects. In a previous study, polysaccharides, phlorotannin, and free sugar (100 μg/mL) from Ecklonia radiata (Ecklonia cava) effectively attenuated Aβ1-42-induced neuronal cell death and enhance neurite outgrowth activity in PC-12 cells ⁽⁵³⁾. Additionally, E. cava extract was found to inhibit AChE and butyrylcholinesterase and showed antioxidant activity against hydrogen peroxide- and AAPH-induced oxidative damage in PC-12 and SH-SY5Y cells ⁽⁵⁴⁾. In another study, the anti-Alzheimer’s disease effects of the brown algae Pandina pavonica extract was observed in an Aβ-induced. SH-SY5Y cell model. The results indicated that pretreatment with the acetone extract of P. pavonica protected the mitochondrial membrane potential, inhibited α-synuclein and tau protein aggregation, and improved the formation of Aβ peptide aggregates in Aβ-induced SH-SY5Y cells ⁽⁵⁵⁾.

4) Marine sponges

Pyridoacridine alkaloid is one of the most abundant chemical constituents of marine-derived alkaloids, commonly obtained from marine sponges, tunicates, anemones, and mollusks. This alkaloid group has been identified as a new major strategy for drug development, including therapies for Alzheimer’s disease, because it can inhibit AChE activity ^(56,57). Petrosamine, a colored pyridoacridine alkaloid isolated from the sponge Petrosia species, exhibits about six times stronger AChE inhibitory activity than galanthamine, the AChE inhibitor currently used in Alzheimer’s therapy, due to its molecular structure ⁽⁵⁸⁾.

Alzheimer’s disease, like Parkinson’s, is a neurodegenerative disorder that affects people worldwide. Despite extensive research, there is a lot of unclear information about the disease, and currently, there are no definitive treatments or preventive method for it. Therefore, this paper attempted to explain the main causes of Alzheimer’s disease, such as Aβ, neuroinflammation, and tau protein, and to suggest a new therapeutic strategy by utilizing the neuroprotective effects of natural products. Drugs such as cholinesterase inhibitors and NMDA antagonists only alleviate the symptoms of Alzheimer’s disease, but they have the limitation that they are only slowing down the progression of the disease without curing it. Researchers are increasingly interested in the neuroprotective effects of natural compounds to address the limitations of existing drugs.

Natural products have been used to treat or improve disease in various fields, including antibiotics and cancer treatment. Compared to synthetic drugs, the synthetic process is reduced, making them cheaper, and their safety is ensured as they have already widely used in many fields. Natural products such as G. biloba, berberine, algae, and marine sponge are expected to have therapeutic effects such as inhibiting Aβ production, preventing tau protein hyperphosphorylation and aggregation, alleviating neuroinflammation, and improving systemic immune responses.

However, research on natural products is still unclear and clinical studies are very insufficient, so further investigation is needed before using them as treatments for Alzheimer’s disease. Researchers are currently making significant efforts to develop and study therapeutic agents using natural products to overcome many limitations. In this paper, we suggest that natural products with a wide range of pharmacological and physiological activities may be one of the therapeutic options for not only Alzheimer’s disease but also various other neurodegenerative diseases through various studies.

None.

No potential conflict of interest relevant to this article was reported.

This research was supported by the National Research Foundation (NRF) funded by the Korean government (No. 2022R1F1A10651621230882063400102).

Conceptualization: HJC. Formal analysis: all authors. Funding acquisition: HJC. Supervision: HJC. Validation: all authors. Writing – original draft: all authors. Writing – review and editing: all authors.