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].

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.

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.

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].

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.

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.

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.

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.