Introduction

The increase in life expectancy has led to an increase in the growth of the number of Alzheimer’s patients. Data show that there are currently an estimated 50 million people with Alzheimer’s disease (AD) worldwide [1], and this number is expected to grow to around 152.8 million by 2050 [2]. AD is a progressive neurodegenerative disease that slowly reduces cognitive and behavioural function, causing impairments in memory, language, and thinking, so patients will have difficulty performing their daily tasks [3, 4]. Short-term memory loss is one of the most common and earliest symptoms of AD, causing patients to have difficulty remembering recent events and learning new information [5]. In addition to affecting cognitive abilities, it also causes behavioural changes such as restlessness, more frequent anxiety, and changes in sleep patterns [5].

The main markers of this disease are amyloid-β (Aβ), which accumulates due to an imbalance between the production and elimination of Aβ in the brain, and Tau protein, which undergoes hyperphosphorylation [6]. Under normal conditions, Aβ is a cell component that is naturally present in cells and can be dissolved and denatured, but under abnormal conditions, for example due to disease, Aβ production becomes excessive, and Aβ protein becomes insoluble [7]. Initially, Aβ plaques form in several parts of the brain, such as the basal, temporal, and orbitofrontal neocortex, and will develop in the hippocampus, amygdala, and basal ganglia at an advanced stage. The presence of Aβ can trigger inflammation, oxidative stress, and neuronal cell death that cause impaired cognitive function [8].

The presence of Aβ plaques also activates kinases that cause hyperphosphorylation of Tau proteins to form neurofibrillary tangles (NFTs) [8]. Tau protein plays a role in tubulin polymerization and microtubule stability, which is part of the cytoskeleton [9], so this protein is very important for maintaining the structure and stability of neurons and also plays an important role in synaptic plasticity [10]. In AD patients, Tau protein is phosphorylated [4, 9] due to increased kinase enzyme activity, which causes microtubule destabilization, impaired cytoplasmic transport, impaired synapse function and morphology, and neurodegeneration [4, 10]. In addition, this also causes the Tau protein to lose the ability to bind microtubules, undergo structural changes, and form NFTs that precipitate in the cytoplasm [10].

Other factors (Figure 1) that can increase the risk of this disease are genetic factors such as chromosome 21 trisomy and ApoE E4 [5], epigenetic factors such as histone deacetylase enzyme activity [11], illness, and unhealthy lifestyles [5]. However, aging is the most important factor in AD because it can lead to a decline in the immune system, making the elderly more susceptible to neuroinflammatory infections [12]. Neuroinflammation is one of the key components in the pathogenesis of AD because neuroinflammation can trigger the activation of microglia [13] and astrocytes [14, 15] and also increase proinflammatory cytokine production that ultimately worsens AD [13].

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Figure 1. The multi-tiered cascade of Alzheimer’s disease (AD). This diagram illustrates the sequential and interrelated events in AD. Upstream risk factors, such as genetic, epigenetic, aging, illness, and lifestyle. Primary pathological features, characterized by accumulation of Aβ plaques and NFTs. Secondary inflammation cascade, such as glial cells activation, pro-inflammatory cytokines, and free-radical. Aβ: amyloid-β; NFT: neurofibrillary tangle.

Although the Food and Drug Administration (FDA) has approved anti-amyloid monoclonal antibodies as a treatment for select patients with early-stage AD, the currently available treatment options still have limitations [16–18]. In addition to relatively moderate clinical benefits and the need for periodic monitoring, various pharmacological therapies are also associated with side effects. Reported side effects vary widely, ranging from gastrointestinal issues, fatigue, and muscle cramps [19] to respiratory failure, which can certainly endanger Alzheimer’s patients [20], to amyloid-related imaging abnormalities (ARIA) associated with monoclonal antibody therapy [16–18]. Based on these conditions, various natural compounds have been extensively studied as therapeutic candidates for AD due to their potential to modulate the molecular mechanisms involved in the pathogenesis of this disease. Some natural ingredients with this potential include curcumin [21, 22], resveratrol [23–27], and luteolin [28–31]. These three natural ingredients are easily found because they are contained in various types of plants. For example, curcumin can be found in Curcuma longa [32–34], resveratrol can be found in berries, nuts, and eucalyptus [23–26, 35], and luteolin can be found in herbs, spices, and flowers [29–31, 36].

Curcumin, resveratrol, and luteolin can cross the blood-brain barrier (BBB) through transmembrane diffusion [37] because these compounds are low-molecular-weight, non-dissociative, and lipophilic molecules [38]. These three compounds are also polyphenols that play a role in various biological pathways and show therapeutic potential against a range of diseases, including cancer, inflammatory conditions, and neurodegenerative diseases, through the modulation of various molecular mechanisms, including the activation of glial cells in AD [39–41]. This review article aims to present research evidence on how curcumin, resveratrol, and luteolin modulate glial activation and neuroinflammatory pathways associated with AD, and to review the potential of these three compounds as candidates for natural neuroprotective agents.

Search strategy and study selection

This review article follows a literature search and selection process informed by the PRISMA guidelines to enhance the transparency and reproducibility of the article identification and selection process. The aim is to improve the transparency of the literature search and study selection process. Literature was obtained from reputable electronic databases, namely PubMed, Scopus, ScienceDirect, and ResearchGate, covering the last ten years (2015–2025), except for seminal articles that provide important scientific insights into the molecular mechanisms or biological activities of the compounds under review. The keywords used in the literature search involved the following combination of Boolean operators: (“Natural Compounds” OR “Curcumin” OR “Resveratrol” OR “Luteolin”) AND (“Molecular Mechanism” OR “Glial Activation” OR “Neuroinflammation” OR “Inflammation”) AND (“Alzheimer’s Disease”).

The literature selection process was conducted in several stages: the identification stage (collecting literature from databases, recording it, and checking for duplicate entries), the screening stage (screening titles and abstracts to eliminate irrelevant articles, while non-AD mechanistic studies are still considered if they discuss biological pathways involved in the pathogenesis of AD), the eligibility stage (reviewing the full text of the remaining articles to ensure compliance with inclusion criteria and eliminating non-compliant articles), and the inclusion stage (articles that meet all the criteria and are then synthesized narratively to explain the molecular mechanisms and evaluate the therapeutic potential of curcumin, resveratrol, and luteolin in the context of AD). This review focuses on three compounds—curcumin, resveratrol, and luteolin—because these three compounds meet the following inclusion criteria: (1) they are representative compounds of different chemical classes (curcumin: diarylheptanoids; resveratrol: stilbenes; and luteolin: flavonoids); (2) they possess consistently demonstrated bioactivity in modulating major neuroinflammatory pathways; and (3) they have comprehensive preclinical study data available, allowing for a systematic analysis of molecular mechanisms compared to other compounds.

Based on these considerations, inclusion and exclusion criteria were established to ensure that the selected literature remained relevant. Studies were included if they addressed the functions of curcumin, resveratrol, or luteolin related to glial cell activation, neuroinflammation, molecular mechanisms, or neuroprotective effects relevant to the pathogenesis of AD. In addition to studies using direct models of AD, mechanistic in vitro and in vivo studies evaluating AD-related molecular pathways (e.g., oxidative stress, microglial activation, inflammation, mitochondrial dysfunction, and apoptosis) are also considered if they provide information that supports an understanding of how these compounds work in the context of AD. English-language articles with full-text access were prioritized, including articles on experimental, preclinical, and review studies relevant to the topic. Meanwhile, articles were excluded if they did not discuss molecular mechanisms relevant to the pathogenesis of AD or did not provide information on the biological activities of curcumin, resveratrol, or luteolin related to neuroinflammation, glial cell activation, or neuroprotection. Additionally, duplicate publications, conference abstracts, and non-scientific reports were also excluded from this review. PRISMA flow diagram in Figure 2 illustrates the entire literature search and study selection process.

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Figure 2. PRISMA flow diagram. PRISMA-based flow diagram illustrating the literature search and study selection process for articles related to curcumin, resveratrol, and luteolin in the modulation of glial activation and neuroinflammatory pathways in Alzheimer’s disease. Adapted from https://www.prisma-statement.org/. Accessed May 8, 2026. © 2024-2026 the PRISMA Executive. Licensed under a CC BY 4.0.

Neuroinflammation

Based on its etymology, inflammation, which comes from the Latin inflammo, means to ignite. Inflammation is a complex biological response of the immune system that arises in response to pathogens, tissue damage, toxic compounds, or radiation, and is characterized by clinical manifestations such as redness, edema, increased temperature, pain, and impaired function of the affected tissue [42]. The inflammatory response involves interactions between the lymphoid and vascular systems that play a role in protecting the body from various harmful stimuli by eliminating the cause of inflammation and initiating tissue repair processes [42, 43].

Inflammation can occur in all areas of the body, including the brain, which is called neuroinflammation. Neuroinflammation can be caused by pathological disorders such as infection, trauma, ischemia, and toxic exposure [44, 45], resulting in increased glial cell activation and the release of proinflammatory mediators in the form of cytokines [46]. Based on research conducted by Yuniarti et al. [47] (2025), neuroinflammation can also be triggered by oxidative stress due to ethanol exposure. Neuroinflammation initially serves as a natural defense mechanism when the central nervous system (CNS) experiences an acute event by limiting damage, clearing dead tissue, and initiating the healing process [48, 49]. However, in chronic conditions, persistent inflammation in the nervous system can be detrimental because it has the potential to accelerate neuron degeneration [48, 49].

The neuroinflammatory process is characterized by activation of immune responses in the CNS, involving astrocytes, microglia, BBB endothelial cells, neuronal cells, and the infiltration of peripheral immune cells into the parenchyma of the CNS [44, 49, 50]. Overactivity of glial cells, such as microglia and astrocytes, is a sign of chronic neuroinflammation. Under normal conditions, microglia act as resident immune cells in the brain that constantly monitor the brain’s microenvironment and contribute to maintaining the survival of neurons [14, 45], detect and evaluate inflammatory signals, support synaptic plasticity, and eliminate cell debris through phagocytosis [48]. When harmful stimuli are present, microglia become an activated form called disease-associated microglia (DAM). DAM can increase the expression of certain receptors, chemokines [14], and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6, that play a role in neuroinflammation and neurodegenerative diseases such as AD [49].

Besides microglia, astrocytes may also play a role in neuroinflammation because astrocytes are responsible for maintaining brain homeostasis and providing nutrients and growth factors to neurons [14, 15] and are also involved in the formation of a unique perivascular channel in the CNS known as the glymphatic system. This system functions to eliminate neurotoxic waste products, including Aβ and Tau protein [51]. Astrocytes respond to pathological conditions, such as AD, by forming reactive astrocytes, which are characterized by cell enlargement or hypertrophy as a result of increased expression of glial fibrillary acidic protein (GFAP) [14, 42]. The formation of reactive astrocytes is induced by inflammation through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which then produces inflammatory mediators so that cells lose homeostatic functions and trigger apoptosis of neurons and oligodendrocytes [48, 51]. These glial cells, both microglia and astrocytes, will release various inflammatory mediators, including proinflammatory cytokines, chemokines, and reactive oxygen species (ROS), which contribute to increased neuronal damage and lead to progressive neuronal function decline, as seen in AD [48].

Neuroinflammation in Alzheimer’s disease

The accumulation of Aβ plaques and hyperphosphorylation of Tau proteins lead to microglia activation. Both AD marker proteins are detected by microglia as a threat, so microglia are activated and produce cytokines such as IL-1β, IL-6, and TNF-α [13]. Aβ plaques are surrounded by microglia that will eliminate them through phagocytosis [51]. However, in chronic conditions, Aβ stimulates increased production of various neurotoxic mediators, including ROS, nitric oxide (NO), cytokines, and chemokines, which ultimately exacerbate the inflammatory response [13, 14]. In addition to microglia activation, the presence of Aβ plaques and Tau protein also triggers the activation of astrocytes into reactive astrocytes [14, 15]. Reactive astrocytes are characterized by cell hypertrophy and increased release of neurotoxic factors, which further disrupt the processing of amyloid precursor protein (APP) by astrocytes and ultimately increase the accumulation of Aβ [14].

The combination of over-activation of glial cells can disrupt the integrity of the BBB and increase its permeability, allowing peripheral immune cells, including neutrophils, B lymphocytes, T lymphocytes, and natural killer cells, to infiltrate from the bloodstream into brain tissue [13, 14]. Neutrophils activated by Aβ plaques and neuroinflammatory signals migrate across the damaged BBB, release ROS, and form neutrophil extracellular traps (NETs), which contribute to neuronal damage, BBB dysfunction, and impaired cerebral blood flow [13]. Different from neutrophil cells, T lymphocytes will interfere directly with neurons and disrupt synaptic plasticity, resulting in decreased cognitive function in Alzheimer’s patients by producing proinflammatory cytokines that can increase neuroinflammation and disrupt BBB homeostasis [13]. On the other hand, B lymphocytes have a dual role, both as anti-inflammatory agents through secretion of IL-35 and IgG, and as pro-inflammatory agents through the release of TNF-α, IL-6, and activating microglia [13, 14]. Aβ plaques will also activate NK cells that will interact with microglia and release pro-inflammatory cytokines, further exacerbating neuroinflammation [13]. The mechanism underlying the involvement of glial cells in neuroinflammation in AD is illustrated in Figure 3.

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Figure 3. The mechanism by which glial cells are involved in neuroinflammation in AD. (A) DAM activation mechanism from homeostatic microglia is transformed into stage 1 DAM by unknown signals such as AD. Stage 1 DAM then transforms into stage 2 DAM with the presence of TREM2 signaling. (B) Reactive astrocyte activation from homeostatic astrocytes is mediated by several factors such as amyloid accumulation, microglia activation, mitochondrial fragments, and IL-18. AD: Alzheimer’s disease; Aβ: amyloid-β; DAM: disease-associated microglia; IL-18: interleukin-18; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TREM2: triggering receptor expressed on myeloid cells 2.

Therapeutic potential of natural compounds targeting neuroinflammation

One of the challenges faced in AD therapy is the limited effectiveness of available drugs. Currently, there are two classes of therapeutic drugs used for AD therapy, which are acetylcholinesterase enzyme inhibitors and glutamate receptor antagonists [52]. The drugs used in AD therapy are not optimal because they only reduce the symptoms of AD and also have side effects such as salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis syndrome (SLUDGE syndrome) that can cause difficulty in controlling body movements and respiratory failure [20]. In recent years, disease-modifying therapies in the form of anti-amyloid monoclonal antibodies, such as lecanemab [18] and donanemab [16, 17], have been approved by the FDA for selected patients with mild cognitive impairment or mild dementia due to AD who have been confirmed to have amyloid pathology [16–18]. Although both therapies have been shown to reduce amyloid plaque burden and slow cognitive decline compared to placebo, the resulting clinical benefits remain moderate, and their use is limited to specific patient populations that meet the selection criteria. In addition, these therapies are also associated with the risk of ARIA, including cerebral edema (ARIA-E) and microhemorrhages (ARIA-H), thus requiring periodic monitoring using magnetic resonance imaging (MRI) during treatment [16–18].

Therefore, the development of alternative therapies that are safer, more effective, and applicable to a broader patient population remains a critical need in the management of AD. In this context, natural compounds are gaining increasing attention because they demonstrate promising neuroprotective activity through the modulation of various molecular pathways involved in the pathogenesis of AD. The results of research conducted by Anas et al. [53] (2024) show that natural compounds have the potential to prevent memory decline in neurotoxin-induced animal models. These findings suggest that natural compounds not only have the potential to improve symptoms but also to modulate the mechanisms underlying the development of AD. In addition, natural compounds have been extensively studied for their potential to provide neuroprotective effects through various molecular mechanisms and generally demonstrate promising safety profiles in preclinical studies as well as in some clinical trials. Curcumin, resveratrol, and luteolin are natural compounds that have shown potential as anti-neuroinflammatory agents in AD [23, 28, 45]. All three compounds are reported to inhibit microglia and astrocyte activation [25, 41, 54], inhibit pro-inflammatory enzymes (e.g., COX-2, iNOS), and reduce pro-inflammatory gene expression through suppression of the NF-κB signalling pathway [26, 30, 31, 46]. On the contrary, these compounds activate anti-inflammatory signaling pathways, increase the expression of anti-inflammatory genes, and modulate multiple neuroprotective signaling pathways, including sirtuin 1 (SIRT1)/GSK3β, p38 mitogen-activated protein kinase (MAPK)/NF-κB, and triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/NF-κB [23, 31, 45]. The following is an explanation of the mechanisms of curcumin, resveratrol, and luteolin as anti-neuroinflammatory agents, as well as the studies that support them.

Curcumin

Curcumin (Figure 4) is a natural compound contained in rhizome plants such as Curcuma longa from the Zingiberaceae family, which has potential as a neuroprotective agent [32–34]. This plant can be found in many tropical areas, one of which is in Indonesia [32]. Curcumin has a distinctive chemical structure. Aromatic groups on curcumin play an important role in the biological activity of curcumin [55]. Based on several research results, curcumin is proven to function as an antibacterial, antihepatotoxic, antiviral, antioxidant, anticancer, and anti-inflammatory agent [21, 22, 56]. Curcumin and its analogues have been shown to act as neuroprotective agents by inhibiting HDAC2, which supports neuronal survival, synaptogenesis, and reduces neuroinflammation [47]. Curcumin is also known to be able to penetrate the BBB and is detected in the CNS [47]. This ability is closely related to its structural characteristics, especially the presence of a methoxy group (–OCH₃), which is relatively nonpolar [55]. Curcumin has low polarity but high lipophilicity compared to its derivatives, and these physicochemical differences directly affect the pharmacokinetic profile, where the higher lipophilicity of curcumin supports BBB penetration [57].

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Figure 4. Structure of curcumin. Curcumin has a chemical structure of diferuloylmethane, which is a conjugated heptadiene-3,5-dione chain connecting two identical aromatic rings. (PubChem CID: 969516; 2D/3D structure: https://pubchem.ncbi.nlm.nih.gov/compound/969516).

Curcumin and its analogues have shown potential as anti-Alzheimer’s agents through various multi-target mechanisms, including suppressing glial cell activity, inhibition of the NF-κB/p38 MAPK pathway, activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and increased expression of neprilysin (NEP), which plays a role in Aβ degradation, as well as reducing the release of proinflammatory cytokines such as IL-1β and TNF-α [39]. In studies conducted by Iteire et al. [54] (2022) and Sorrenti et al. [46] (2018), curcumin was shown to reduce the expression of the ionized calcium-binding adapter molecule 1 (Iba1) protein, which is an important marker in microglia activation, so that microglia remain in a resting state and do not cause neuroinflammation. This decrease in Iba1 protein expression occurs because curcumin inhibits TLR4/myeloid differentiation primary response 88 (MyD88)/NF-κB pathway activation [45, 58]. TLR4, which is activated by foreign molecules such as lipopolysaccharide (LPS), activates MyD88, which then activates NF-κB, resulting in increased transcription of inflammatory genes and increased expression of Iba1 protein [58].

Curcumin specifically binds directly to the myeloid differentiation protein-2 (MD-2) co-receptor, preventing LPS from binding to TLR4. As a result, TLR4 dimerization is prevented, so that the danger signal cannot be transmitted to the MyD88 protein [59, 60]. Consequently, the downstream kinase cascade is attenuated, suppressing NF-κB activation and nuclear translocation and reducing the production of pro-inflammatory cytokines [61]. Other studies have also indicated that curcumin and its derivatives (hydroxylated monocarbonyl curcumin) can act as inducers that increase NEP enzyme activity, so it can enable the enzyme to break down and clear Aβ plaques [62]. Suppression of TLR4 expression also can increase TREM2 expression, which functions as an anti-inflammatory microglia receptor in inhibiting pro-inflammatory TLR4 signaling [45]. TREM2 activation tends to promote M2 (anti-inflammatory, neuroprotective) phenotypes, rather than M1 (pro-inflammatory) phenotypes, so that Iba1 protein expression decreases [45]. The mechanism of action of curcumin can be seen in Figure 5.

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Figure 5. The mechanism of action of curcumin. Curcumin inhibits TLR4/MyD88/NF-κB pathway activation by binding to MD-2, which can cause a decrease in the expression of Iba1 protein and proinflammatory cytokines. Curcumin also increases the expression of TREM2, leading to increased anti-inflammatory activation of microglia (M2). Iba1: ionized calcium-binding adapter molecule 1; IL: interleukin; LPS: lipopolysaccharide; MD-2: myeloid differentiation protein-2; MyD88: myeloid differentiation primary response 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TLR4: toll-like receptor 4; TNF-α: tumor necrosis factor-alpha; TREM2: triggering receptor expressed on myeloid cells 2.

In addition to reducing Iba1 expression, curcumin can also reduce the expression of the reactive astrocyte marker, GFAP, which leads to reduced formation of reactive astrocytes that resulting in reduced neuroinflammatory response [54]. Curcumin also suppresses the expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 [46, 49, 63, 64] by inhibiting the activation of the TLR4/NF-κB signal transduction pathway [54]. These proinflammatory cytokines mediate the transformation of astrocytes into reactive astrocytes, so that a decrease in these cytokines prevents the formation of reactive astrocytes and reduces GFAP expression [54]. In Table 1, we can see several studies that prove that curcumin has the potential to attenuate neuroinflammation through various mechanisms.

Table 1. Studies that prove that curcumin has the potential to overcome neuroinflammation.

Researcher and year	Model	Resveratrol dosage and duration	Parameter	Key results	Conclusion
Yu et al., 2018 [49]	Microglia BV-2 cells	5, 10, and 20 µM curcumin, 1-hour pre-incubation, then lipoteichoic acid (LTA) for 16–24 hours	1. Cell viability (MTT assay) 2. NO, PGE2, tumor necrosis factor-alpha (TNF-α) (ELISA/Griess) 3. Expression of iNOS & COX-2 mRNA (qRT PCR) 4. Mitogen-activated protein kinase (MAPK) phosphorylation (p38, ERK, Akt) & nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation 5. HO-1 & nuclear factor erythroid 2-related factor 2 (Nrf2) expression	1. No toxic effect on cell viability 2. Dose-dependent decrease in NO, PGE2, TNF-α 3. Decreased iNOS and COX-2 mRNA expression 4. Inhibits phosphorylation of MAPK & translocation of NF-κB 5. Increases the expression of HO-1 and Nrf2; inhibition of HO-1 eliminates the anti-inflammatory effect of curcumin	Curcumin suppresses microglia activation and inflammatory mediator production by inhibiting NF-κB and MAPK pathways, as well as induction of the HO-1/Nrf2 antioxidant pathway, making curcumin a potential candidate for anti-neuroinflammatory therapy
Kharazmi et al., 2022 [65]	Wistar male rats	10 mg/kg BW curcumin, oral (gavage), 35 days pretreatment before morphine injection	1. Latency of inhibitory avoidance (IA memory) 2. Motor activity (open field) 3. Expression of p-CREB & total CREB in hippocampus 4. NOx (nitric oxide metabolite) levels in brain tissue	1. Pre-treatment with curcumin prevents latency decrease 2. No significant change in motor activity between groups 3. Increased p-CREB, supporting its protective role against memory 4. Increases NOx levels, possibly activating the NO → p-CREB → memory signaling pathway	Curcumin prevents morphine-induced memory impairment in mice, likely through increased NO and activation of downstream CREB signaling
Namgyal et al., 2020 [63]	Swiss albino mice; Cadmium (Cd) exposure	Oral curcumin (oral gavage) at various doses; Cd exposure 2.5 mg/kg BW for 60 days	1. Behavior (spontaneous alternation, elevated plus-maze) 2. Antioxidant enzyme SOD, CAT, and GSH levels and malondialdehyde (MDA) level 3. Inflammatory cytokine levels (IL-6, TNF-α, IL-10) 4. Histology of prefrontal cortex neurons	1. Working memory and anxious behavior improved in rats given curcumin 2. SOD, CAT, and GSH activities increased; MDA activity decreased 3. IL-6 and TNF-α decreased; IL-10 increased 4. Neuron morphology in the prefrontal cortex improved	Curcumin protects cognitive function and prefrontal neuron structure by reducing oxidative stress and neuroinflammation due to Cd exposure
Sorrenti et al., 2018 [46]	Young adult mice	50 mg/kg BW curcumin, orally, given 2 consecutive days before LPS injection (5 mg/kg i.p.)	1. Microglia activation (Iba1) 2. Proinflammatory cytokines 3. Physical symptoms (sickness behavior) 4. Long-term memory function (Morris Water Maze)	1. Decreased microglia activation (seen from decreased Iba1 expression and improved cell morphology) 2. Significant reduction in IL-1β and TNF-α expression in plasma and brain tissue 3. Reduced symptoms of sickness behavior faster than the LPS group without curcumin 4. Accelerated long-term memory recovery even though it was only given briefly	Short-term preventive curcumin effectively suppresses LPS-induced acute neuroinflammation and reduces long-term memory consequences

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Resveratrol

Resveratrol (Figure 6) is a polyphenol that can be found in 72 plant species spread across 31 genera and 12 families [66]. Some plants that contain resveratrol include grapes, blueberries, cranberries, nuts, and eucalyptus [23–26, 35]. The structure of resveratrol consists of two aromatic rings connected by a methylene bridge [66]. Resveratrol has several biological functions such as anti-aging, anti-cancer, anti-inflammatory, antioxidant [23–27], anti-neurodegenerative [23], antiviral [25], and anti-apoptotic [25, 26]. In addition, due to its ability to penetrate the BBB, resveratrol can exert neuroprotective effects [25]. Resveratrol is lipid soluble and has a molecular weight of 228 Da, so it easily crosses the BBB via transmembrane diffusion [67]. Therefore, resveratrol may be a candidate for AD therapy [68].

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Figure 6. Structure of Resveratrol. Resveratrol has a basic structure of trans-3,5,4'-trihydroxystilbene, which consists of two aromatic rings connected by an ethylene bridge. (PubChem CID: 445154; 2D/3D structure: https://pubchem.ncbi.nlm.nih.gov/compound/445154).

Resveratrol has several mechanisms of action in reducing neuroinflammation. Based on studies performed by Chen et al. [25] (2023) and Yang et al. [40] (2017), resveratrol can reduce neuroinflammation through the mechanism of microglia polarization from M1 phenotype to M2 phenotype. It can suppress the production of M1 microglia and induce M2 microglia production, resulting in a decrease in proinflammatory cytokines and an increase in anti-inflammatory cytokines so that the brain tissue can be protected from damage due to inflammation [25]. More specifically, resveratrol activates the SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) pathway [23]. SIRT1 is a deacetylase enzyme that has a role in oxidative stress regulation, inflammation, and cell survival [26]. Administration of resveratrol to mice with AD has been reported to increase SIRT1 expression in the hippocampus [23].

Resveratrol directly activates SIRT1, which then deacetylates the p65 subunit of NF-κB, reducing the transcription of pro-inflammatory genes [69, 70]. SIRT1, which has been activated by resveratrol, also releases the acetyl group bound to PGC-1α, activating PGC-1α and making it a transcription coactivator [69, 71]. Activation of PGC-1α can suppress the expression of the BACE1 enzyme, which plays a role in the formation of Aβ plaques, preventing the formation of Aβ plaques [72]. The mechanism of action of resveratrol can be seen in Figure 7.

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Figure 7. The mechanism of action of resveratrol. Resveratrol activates SIRT1, which then deacetylates the p65 subunit of NF-κB and reduces the expression of pro-inflammatory cytokines. Resveratrol-activated SIRT1 also enhances PGC-1α activation, reducing BACE1 expression, which leads to a decrease in Aβ plaque formation. Aβ: amyloid β; IL: interleukin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; SIRT1: sirtuin 1; TNF-α: tumor necrosis factor-alpha.

Increased PGC-1α expression also may lead to decreased NF-κB activation so that transcription of M1 proinflammatory genes is reduced while transcription of M2 anti-inflammatory genes is increased. As a result, the polarization shifts from M1 to M2 [40]. Another study explained that resveratrol is capable of inducing deacetylation of p65 NF-κB and signal transducer and activator of transcription 3 (STAT3), which act as major transcription factors of proinflammatory cytokines [26]. This deacetylation process suppresses the transcription of proinflammatory genes, including TNF-α, IL-1β, and COX-2, contributing to a reduction in neuroinflammation levels [26]. In addition, resveratrol modulates downstream signaling pathways, including PI3K/Akt, and regulates GSK-3β phosphorylation, contributing to a reduction in Tau protein hyperphosphorylation [23]. Table 2 shows several studies that prove that resveratrol has the potential to attenuate neuroinflammation through various mechanisms.

Table 2. Studies that prove that resveratrol has the potential to overcome neuroinflammation.

Researcher and year	Model	Resveratrol dosage and duration	Parameter	Key results	Conclusion
Moussa et al. 2017 [68]	Mild-moderate Alzheimer’s subjects (human, N = 119; subset analysis N = 19 vs. 19)	Up to 2 g per day (1 g twice daily), 52 weeks duration	1. CSF markers MMP-9, MDC, IL-4, FGF-2 2. Plasma MMP-10, IL-12P40, IL-12P70, RANTES 3. Mini-Mental Status Examination (MMSE) & AD Cooperative Study-Activity of Daily Living (ADCS-ADL) scores 4. CSF Aβ-42, Aβ-40, Tau	1. Significant decrease in CSF MMP-9 2. Increase in MDC, IL-4, FGF-2 in CSF 3. Increased plasma MMP-10; decreased IL-12P40, IL-12P70, RANTES 4. Slow decline in MMSE, ADCS-ADL, CSF Aβ-42; did not affect Tau	Resveratrol decreases neuro-inflammation, enhances adaptive immune responses, and stabilizes cognitive decline and AD biomarkers; sirtuin 1 (SIRT1) activation has potential as a therapeutic target
Abozaid et al. 2022 [23]	Wistar rats, AD model induced by AlCl3 (100 mg/kg/day for 60 days)	Oral RSV-SeNPs, 200 mg/kg/day via gavage for 8 weeks (after AD formation)	1. Oxidative stress: MDA, GSH, catalase 2. AD biomarkers: Aβ-42, p-Tau 3. Neuroinflammation: IL-1β, p-STAT3 4. Cholinergic: ACh 5. Cell signaling: p-PI3K, p-GSK-3β 6. Gene expression: SIRT1, miR-134 (RT-qPCR) 7. Histopathology: hippocampus (Aβ plaques, neuronal hypoplasia vs. protection)	1. RSV-SeNPs reduce MDA, increase GSH & catalase 2. Lower Aβ-42 & p-Tau levels 3. Reduced IL-1β and p-STAT3 (decreased neuroinflammation) 4. Increased brain ACh 5. Restoring p-PI3K and p-GSK-3β to normal direction 6. Increases SIRT1 expression, suppresses miR-134 7. Histopathology: reduced Aβ plaques and neuronal degeneration in the hippocampus, as well as increased healthy neurons	RSV nano-formulation with selenium effectively ameliorated oxidative stress, neuroinflammation, cholinergic effects and AD biomarkers in Alzheimer’s mouse models. Mediated through activation of the PI3K pathway/suppressing GSK-3β, modulation of SIRT1/miR-134, and decreased
Chen et al. 2023 [25]	In vivo: 6-week-old female ICR mice (Institute of Cancer Research mice); azq: primary microglia (neonatal ICR), primary neurons; PRV (pseudorabies virus)	In vivo: Res were given oral gavage pre-treatment 7 days before PRV intranasal infection, then continued 1×/day for 3 days after infection; In vitro: Res 3.75, 7.5, 15 µg/mL [incubation 24–48 h; CCK-8 (Cell Counting Kit-8): 0–60 µg/mL]	1. Blood-brain barrier (BBB)/edema: brain water content, Evans blue extravasation; IHC MMP-2, MMP-9, ZO-1, Iba1 2. Histologi: H&E, Nissl, TUNEL (neuronal apoptosis) 3. Inflamasi/sitokin: mRNA (RT-PCR) & protein (ELISA) untuk IL-6, tumor necrosis factor-alpha (TNF-α), CCL3, CXCL10, MCP-1, IL-4, IL-10, TGF-β, NGF, GDNF 4. M1/M2 microglia: immunofluorescence & flow cytometry (CD11b, CD86 as M1; CD206 as M2); mRNA M1 markers (CD86, TNF-α, iNOS) & M2 markers (CD206, Arg-1, Ym1) 5. Co-culture: inflamasi neuron (ELISA) & apoptosis neuron (AnnexinV/PI)	1. BBB & brain edema: medium- and high-dose Res decreased brain water content; high-dose Res decreased BBB leakage; Res decreased MMP-2, MMP-9, and increased ZO-1 2. Histology & apoptosis: medium- and high-dose Res reduced neuronal damage and apoptosis 3. Cytokines & inflammation: Res decreases proinflammatory cytokines and increases anti-inflammatory and neurotrophic factors 4. Microglia polarization: Res decreases M1 and increases M2 5. Neuronal co-culture: Res decreases proinflammatory cytokines in neurons; Res increases anti-inflammatory cytokines in neurons; Res reduces neuronal apoptosis	Resveratrol protects against PRV-induced encephalitis in mouse models by repairing BBB integrity, suppressing pro-inflammatory responses, increasing anti-inflammatory cytokines & neurotrophic factors, and shifting microglia polarization from M1 phenotype to M2 phenotype, thereby reducing neuronal apoptosis. These results support the potential of Res as an adjuvant therapeutic agent in viral encephalitis

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Luteolin

Luteolin (Figure 8) is a flavonoid compound derived from plant secondary metabolites [36]. This compound can be found in many plant sources, including herbs such as parsley, peppermint, oregano, thyme; vegetables such as celery seeds, peppers, carrots, and broccoli; spices such as cardamom and anise/fennel; and flowers such as chrysanthemums [29–31, 36, 73]. For those plants, luteolin is used to protect against UV radiation and attract pollinators and seed dispersers [36]. Luteolin exhibits a variety of biological activities, including antioxidant, anti-inflammatory, and neuroprotective [28–31, 73]. Multiple studies have demonstrated that luteolin can inhibit the production of inflammatory cytokines in various neurological disease models, including the AD model [28–30, 73]. Due to its relatively low molecular weight (286.24 Da) [74] and moderate lipophilicity, luteolin possesses physicochemical properties that favor BBB penetration. Indeed, experimental studies have demonstrated that peripherally administered luteolin is capable of crossing the BBB and accumulating in brain tissue [75].

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Figure 8. Structure of Luteolin. Luteolin has a basic structure of 2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one, consisting of three main rings. (PubChem CID: 5280445; 2D/3D structure: https://pubchem.ncbi.nlm.nih.gov/compound/5280445).

Luteolin may act as an anti-neuroinflammatory through several mechanisms, such as modulation of astrocytes [29, 41, 76] and suppression of proinflammatory cytokine production [28, 29, 31, 73]. In AD, the presence of Aβ and phosphorylated Tau proteins can lead to activation of the endoplasmic reticulum (ER) stress pathway characterized by GRP78 (ER stress marker), CHOP (ER stress-related pro-apoptotic protein), and phosphorylation of protein kinase RNA-activated-like ER kinase (PERK), inositol-requiring enzyme 1 alpha (IRE1α), and eukaryotic initiation factor 2 alpha (eIF-2α) [28]. Luteolin prevents the phosphorylation of PERK and eIF-2α, halting the induction of the pro-apoptotic transcription factor CHOP and ensuring that nerve cells are spared from programmed cell death [77]. Luteolin can also directly enhance IRE1α activation and lead to increased splicing of XBP1 into its active form, XBP1s [78], which enhances ER proteostasis by upregulating molecular chaperones and components of the ER-associated degradation (ERAD) pathway [79]. Activation of the ER stress pathway also can trigger the change of astrocytes into reactive astrocytes, resulting in increased expression of GFAP [29, 41, 76], which leads to increased production of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α [28, 29, 41]. Luteolin can prevent the activation of reactive astrocytes [29, 41, 76] and also inhibit ER stress pathway activation so that the production of proinflammatory cytokines decreases [28]. The mechanism of action of luteolin can be seen in Figure 9.

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Figure 9. The mechanism of action of Luteolin. Luteolin inhibits the activation of the PERK pathway and prevents cell death. Luteolin also enhances the IRE1 activity and increases ER capacity to refold or degrade misfolded Aβ proteins. Aβ: amyloid-β; eIF-2α: eukaryotic initiation factor 2 alpha; ER: endoplasmic reticulum; IRE1: inositol-requiring enzyme 1; PERK: protein kinase RNA-activated-like ER kinase.

In addition to modulating astrocyte activity, luteolin suppresses neuroinflammation through inhibition of p38 MAPK phosphorylation [31, 41]. In pathological conditions such as AD, activation of p38 MAPK can trigger the phosphorylation of transcription factors, which in turn increases the expression of proinflammatory cytokines and exacerbates the neuroinflammatory response [31, 41]. By inhibiting the p38 MAPK pathway, luteolin reduces the transcription of proinflammatory cytokines [31, 41]. Luteolin also reduces the expression of adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which play important roles in the leukocyte recruitment to the brain during inflammation, thereby reducing the infiltration of immune cells into the CNS [31]. In Table 3, we can see several studies that prove that luteolin has the potential to attenuate neuroinflammation through various mechanisms.

Table 3. Studies that prove that luteolin has the potential to overcome neuroinflammation.

Researcher and year	Model	Luteolin dosage and duration	Parameter	Key results	Conclusion
Che et al., 2020 [41]	In vitro: murine astrocyte cell line (C8-D1A), activated with LPS	Apigenin & luteolin: 30 μM and 60 μM (pretreatment 1 hour before LPS) Evaluation at 30 minutes, 3 hours, 12 hours, and 24 hours depending on the assay	1. Cell viability 2. Astrocyte activation 3. IL-31 & IL-33 mRNA expression 4. IL-31 & IL-33 protein expression 5. IL-31 & IL-33 secretion 6. Phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), STAT3 7. Translocation & DNA-binding of NF-κB/STAT3 8. Effects of pharmacological inhibitors on signaling pathways	1. Apigenin safe ≤ 60 μM, luteolin safe ≤ 100 μM 2. Apigenin → suppresses ERK, NF-κB, STAT3; more effectively suppresses IL-33 3. Luteolin → suppresses ERK, JNK, p38, NF-κB, STAT3; more effectively suppresses IL-31 4. Both decrease IL-31 & IL-33 secretion, inhibit NF-κB/STAT3 translocation to the nucleus, and decrease DNA-binding activity. Both decrease IL-31 & IL-33 secretion, inhibit NF-κB/STAT3 translocation to the nucleus, and decrease DNA-binding activity	Apigenin and luteolin inhibited LPS-induced astrocyte activation and decreased IL-31 & IL-33 production through modulating MAPK, NF-κB, and STAT3 pathways. Both have potential as neuroprotective agents.
Ma et al., 2025 [29]	In vitro: primary cultures of neurons, astrocytes, microglia, as well as mixed cultures of neuron-glia from rat brain	CdCl2 as an inducer of neurotoxicity Luteolin: 5–20 μM (pre-treatment) Treatment duration varies according to test (24–48 hours)	1. Neuron viability (survival assay) 2. Neuron morphology (branching, cell body size) 3. Glia markers: glial fibrillary acidic protein (GFAP) (astrocytes), Iba1 (microglia) 4. Proinflammatory cytokines: tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6 5. Neuronal apoptosis: active caspase-3	1. Luteolin increases neuron survival and maintains healthy morphology 2. Luteolin decreases GFAP expression and suppresses Iba1 expression 3. Luteolin decreases the levels of proinflammatory cytokines 4. Luteolin decreases caspase-3 expression 5. Luteolin maintains neuronal survival	Luteolin reduces Cd neurotoxicity by suppressing glial inflammation and protecting neurons from apoptosis, thus supporting neuronal survival. Potential as a neuroprotective agent.
Facchinetti et al. 2022 [76]	In vitro: co-culture primary astrocytes & oligodendrocyte precursor cells (OPCs) from the brains of Sprague-Dawley rat pups	Co-Ultramicronized Palmitoylethanola-mide/Luteolin (Co-ultra PEALut) PEA: Luteolin = 10:1; 3 µM; 48 hours	1. Viability of astrocytes & OPCs (neutral red assay) 2. Protein & mRNA expression of astrocytes: GFAP, calcium-binding protein B (S100B), glutamine synthetase (GS), HMGB1, IL-6, IL-1β, NF-κB, FGF-2, TGF-β (WB, RT-qPCR) 3. Maturation of OPCs (MBP+/Olig2+ ratio) 4. Oligodendrocyte morphology (surface area, branching/Sholl analysis)	1. Co-ultra PEALut keeps viability normal 2. Co-ultra PEALut suppresses the increase of astrocyte reactivity markers; decreases the expression of proinflammatory cytokines; prevents the decrease of FGF-2, a PPAR-α-independent effect 3. Co-ultra PEALut normalizes MBP+/Olig2+ ratio 4. Co-ultra PEALut prevents cell shrinking & reduced branching	Co-ultra PEALut (PEA + luteolin) normalizes astrocyte-oligodendrocyte communication through anti-inflammatory, pro-trophic, and protective mechanisms. Part of the effect is PPAR-α mediated.
Zhang et al. 2017 [31]	In vitro: human brain microvascular endothelial cells (hBMECs) as a blood-brain barrier (BBB) model	Luteolin: 10 µM, pre-treatment before fAβ1–40	1. Cell viability (MTT assay) 2. Proinflammatory cytokines (IL-1β, IL-6, TNF-α) 3. Adhesion molecules (ICAM-1, VCAM-1) 4. Activation of NF-κB (p65 nuclear translocation) 5. Activation of p38 MAPK (phosphorylation)	1. fAβ1–40 did not decrease cell viability, but increased secretion of IL-1β, IL-6, TNF-α, and expression of ICAM-1 and VCAM-1 2. fAβ1–40 activated p38 MAPK and NF-κB 3. Luteolin decreases cytokines and adhesion molecules, inhibits p38 MAPK phosphorylation, and prevents NF-κB p65 translocation to the nucleus 4. The effects of luteolin are similar to those of a p38 MAPK inhibitor	Luteolin inhibits fAβ1–40-triggered inflammation at the BBB by suppressing the p38 MAPK-NF-κB pathway, thereby decreasing proinflammatory cytokines and adhesion molecules.

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Based on the results of research that has been conducted, the three natural ingredients described above, namely curcumin, resveratrol, and luteolin, have been reported to reduce neuroinflammation. However, these three natural ingredients have different mechanisms of action in overcoming neuroinflammation. In Table 4 below, we can see the differences in the mechanisms of action of these three natural ingredients.

Table 4. Comparative table summarizing the mechanisms of action of the three natural compounds.

Pathway category	Molecular targets/Signaling pathways	Curcumin	Resveratrol	Luteolin
Anti-inflammatory	Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway	Inhibits upstream activation via the toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex	Deacetylation of the p65 subunit via sirtuin 1 (SIRT1) activation	Directly inhibits IKKβ kinase activity
Anti-aging	SIRT1/AMPK/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)	Indirect modulation	Primary activator: Increases the NAD+/NADH ratio and SIRT1 activity	Indirect activation through the reduction of oxidative stress
Glial modulation	Microglia & astrocyte phenotype	Promotes M2 polarization by increasing triggering receptor expressed on myeloid cells 2 (TREM2)	Preventing the pro-inflammatory microglial phenotype via SIRT1	Inhibits astrocyte reactivity (A1) by reducing glial fibrillary acidic protein (GFAP)
Proteostasis	Autophagy & degradation	Increasing the expression of the enzyme neprilysin (NEP) for the degradation of Aβ	Inducing autophagy through AMPK activation	Enhancing the ERAD pathway through IRE1α/XBP1s activation
Organelle stress	Endoplasmic reticulum (ER) & mitochondrial stress	Maintaining intracellular calcium homeostasis	Protecting mitochondria from oxidative damage via nuclear factor erythroid 2-related factor 2 (Nrf2)	Key regulator: Inhibits the protein kinase RNA-activated-like endoplasmic reticulum kinase (PERK)/CHOP pathway (ER stress)
Tau pathology	GSK-3β/Tau phosphorylation	Inhibits the physical aggregation of Tau filaments	Reduces Tau acetylation, which facilitates its clearance	Direct inhibitor: Binds to the ATP-binding site of GSK-3β

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In addition to providing neuroprotective effects through the mechanisms described earlier, curcumin, resveratrol, and luteolin have also been reported to potentially provide neuroprotective effects through modulation of the gut-brain axis. The gut-brain axis is a highly complex two-way communication system between the CNS and the enteric nervous system [80]. This communication occurs through four pathways: the neural pathway (vagus nerve), the immune pathway, the endocrine pathway, and the metabolic pathway [81, 82]. In the gut-brain axis, the composition of the microbiota—particularly bacteria—in the gut plays a crucial role in determining whether these bacteria will act as neuroprotective agents or, conversely, as agents that increase the risk of AD [80]. In a balanced state (eubiosis), bacteria produce neuroprotective substances such as short-chain fatty acids (SCFAs) [80–82], maintain a tight intestinal barrier, and modulate the immune system [80]; however, in an imbalanced bacterial composition (dysbiosis), bacteria produce toxins such as LPS and bacterial amyloid that can cause the intestinal barrier to become permeable (leaky gut), allowing LPS to enter the bloodstream and trigger systemic inflammation, ultimately damaging the BBB [80–82] and inducing neuroinflammation that exacerbates amyloid plaque formation [81]. Examples of bacteria that can provide neuroprotective effects include bacteria from the class Mollicutes, genus Ruminiclostridium 9, genus Clostridium innocuum, and genus Eggerthella; whereas examples of bacteria that can increase the risk factors for AD include bacteria from the order Selenomonadales, family Pasteurellaceae, and genus Methanobrevibacter [80].

Curcumin acts as a detoxifying agent by enhancing the activation of intestinal alkaline phosphatase (IAP), allowing LPS produced by bacteria to be broken down and neutralized before it enters the bloodstream [83]. The reduction of LPS in the gut by curcumin prevents metabolic endotoxemia, which can trigger inflammation in the brain and reduce amyloid plaques [82, 83]. Additionally, curcumin works by modulating the gut microbiota composition and increasing beneficial bacteria such as Bacteroides and Lactobacillus, helping to create an anti-inflammatory gut environment [83, 84]. Meanwhile, resveratrol works by improving the physical structure of the intestinal wall through increased production of tight junction proteins, such as zonula occludens-1 (ZO-1) and occludin, which function to seal the gaps between intestinal cells, preventing leaky gut [84, 85]. Like curcumin, resveratrol also modulates gut microbiota by suppressing harmful bacteria that produce trimethylamine N-oxide (TMAO), which can damage brain blood vessels [86], and increasing bacteria that produce SCFAs, which can cross the BBB and act as anti-inflammatory agents [85, 86]. Furthermore, luteolin also exerts immunomodulatory effects by increasing the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a receptor that suppresses excessive immune responses [87]. Luteolin also exerts neuroprotective effects by alleviating neuroinflammation and cognitive impairment through the inhibition of ER stress-dependent inflammatory signalling [28], as well as the TLR4/TRAF6/NF-κB and p38 MAPK-mediated NF-κB pathways. These mechanisms subsequently reduce the production of pro-inflammatory cytokines and mediators, thereby attenuating neuroinflammation in experimental models of AD and other neurological disorders [28, 30, 31].

These three natural compounds have been shown to act as neuroprotective agents through several mechanisms, making them potential treatments for AD, but several clinical studies have shown different results. Curcumin has been reported to be well tolerated in clinical trials (ClinicalTrials.gov Identifier: NCT00099710). However, various studies have not yet shown any significant improvement in cognitive function, behavior, or AD-related outcomes [88]. Another study (Identification number: ACTRN12611000437965) also noted that curcumin supplementation cannot prevent cognitive decline over a 12-month period [89]. The suspected cause is that curcumin has very low bioavailability, meaning it cannot be absorbed well by the body and ultimately fails to demonstrate efficacy [88]. Curcumin has very low water solubility, approximately 11 ng/mL [90]; it is unstable at physiological pH and sensitive to light, so it can degrade before it can exert a therapeutic effect [90]. Furthermore, curcumin pharmacokinetic data indicate a very short half-life; curcumin concentrations drop sharply from 1.276 µg/mL to just 0.192 µg/mL within 1.5 hours [91]. Results from another human study (Identification number: NCT03085680) indicate that even a single oral dose of 4 g fails to produce significant levels of parent curcumin in the blood (< 0.1 ng/mL) [92]. The issue of low curcumin bioavailability can be addressed through several approaches, including encapsulation techniques to protect curcumin, such as nano-complexation, gelation, and complex coacervation [90]; liposomal formulations that significantly improve the stability and biological distribution of curcumin [91]; and the use of bio-enhancers, such as piperine, to inhibit the rapid metabolism of curcumin [92].

Clinical research on resveratrol shows results that are not much different from curcumin. Resveratrol supplementation has been reported to improve psychomotor speed (ClinicalTrials.gov Identifier: NCT01126229), but does not show any improvement in more complex cognitive domains [93]. Other studies (ClinicalTrials.gov Identifier: NCT01504854) show that resveratrol exhibits a good safety and tolerability profile even when administered at high doses for one year; however, its impact on AD biomarkers and clinical outcomes remains limited and shows inconsistent results [94]. Clinical studies on resveratrol are still pilot studies, so the results shown are not yet consistent with preclinical studies. However, these pilot studies provide justification for further studies with larger designs, longer durations, or different populations to explore other effects [93].

Unlike curcumin and resveratrol, which have begun to be studied clinically, research related to luteolin is still limited to preclinical studies. Luteolin has been shown to have potential as a neuroprotective agent [29, 31], but clinical research on this potential has not yet been widely conducted. Therefore, clinical research on luteolin is needed to support preclinical research results.

Limitations and future perspectives

Research on natural compounds with potential anti-neuroinflammatory effects in AD still faces several limitations. Most studies are confined to in vitro experiments and animal models, so evidence regarding the therapeutic effects of natural compounds in humans remains limited. Differences in glial cell morphology, disease progression, and pharmacokinetics between animal models and humans also pose challenges that ultimately hinder clinical translation.

Another challenge in using natural compounds as neuroprotective agents is their low bioavailability and rapid metabolism, which hamper absorption and make it difficult for these compounds to reach therapeutic concentrations in brain tissue. Additionally, the wide variability in research methodologies—ranging from differences in dosage, duration of administration, animal models, and measured parameters—makes direct comparison of study outcomes difficult. Existing studies have also not focused directly on glial activation, resulting in limited comprehensive mechanistic understanding.

Given these issues, future research could focus on developing nano-based formulations (such as nanoencapsulation, liposomes, and SNEDDS) to increase the bioavailability and stability of natural compounds, thereby improving their absorption and penetration across the BBB. This would subsequently increase the therapeutic concentrations of natural compounds in brain tissue. Furthermore, large-scale clinical studies must begin to evaluate safety, effectiveness, optimal dosing, and long-term therapeutic responses in Alzheimer’s patients to provide more substantial evidence of the neuroprotective potential of these natural compounds. Clinical studies may also be integrated with precision medicine approaches to account for individual genetic variations that influence responses to natural compounds.

Conclusions

Neuroinflammation has an important role in AD, which is influenced by various mechanisms such as activation of glial cells (microglia and astrocytes) and neuroinflammatory signalling pathways (NF-κB and MAPK), so that neuroinflammation can be used as a target for AD therapy. Several natural compounds, such as curcumin, resveratrol, and luteolin, have been shown to have the potential to inhibit neuroinflammation through different mechanisms. Curcumin has been reported to inhibit neuroinflammation by inhibiting the activation of the TLR4/MyD88/NF-κB pathway and suppressing microglia activity. Resveratrol has been reported to reduce neuroinflammation through modulation of the SIRT1 pathway and microglia polarization. Luteolin has been reported to suppress the activation of reactive astrocytes and inhibit p38 MAPK phosphorylation, thereby potentially reducing neuroinflammation. These three natural compounds have been reported to modulate glial cell activity and the expression of proinflammatory cytokines, thus potentially contributing to the control of neuroinflammation and providing neuroprotective effects. Therefore, further research is needed to evaluate the potential of these natural compounds as candidates for natural-based interventions in the treatment of AD.