Потенциальные цели микроглии в лечении нейродегенеративных заболеваний: механизм и терапевтические последствия.

Introduction

Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining neural homeostasis, clearing cellular debris, and mediating neuroinflammatory responses (Isik et al., 2023). The primary functions include synaptic pruning, tissue repair, phagocytosis, and communication with other cellular entities (Wright-Jin and Gutmann, 2019). In neurodegenerative disorders, the aggregation of pathological proteins can provoke microglial activation, triggering the production of pro-inflammatory mediators and exacerbating neuroinflammation (Liu et al., 2022b). Conversely, microglia also exhibit neuroprotective properties; when activated, they can release neurotrophic factors that promote neuronal growth, survival, and the maintenance of neuronal functions while clearing toxic substances from the extracellular environment.

Recent studies have unveiled novel strategies for modulating microglial activity. Specifically, the progression of neurodegenerative diseases may be attenuated or even reversed by suppressing the release of specific inflammatory mediators, enhancing the production of neurotrophic factors, or directly modifying microglial activation states (Polymeropoulos et al., 1997). These approaches aim to mitigate pathological neuronal damage and facilitate effective intervention and treatment during the early stages of the disease.

This review primarily summarizes the function of microglial cells among neurodegenerative diseases, focusing on regulatory factors associated with microglial inflammation. Particular attention is given to the impact of spleen tyrosine kinase (SYK), synaptotagmin-11 (Syt11), and stimulator of interferon genes (STING) on microglial activation and the neuroinflammatory responses they elicit in Parkinson’s disease (PD). Additionally, the research explores the functions and potential mechanisms of emerging types of cell death, including ferroptosis, cuproptosis, disulfidptosis, and parthanatos, in the context of microglial function. A thorough understanding of the temporal dynamics of these regulatory factors and novel forms of cell death is essential for elucidating the mechanisms by which microglia contribute to PD pathogenesis. Furthermore, this research reviews the function of microglial cells among various neurodegenerative disorders, like Alzheimer’s disease (AD), PD, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lewy body dementia (LBD), and Huntington’s disease (HD). Concurrently, analyzing the historical evolution of research about these elements will enhance our comprehension of their respective roles.

Search Strategy

We conducted a systematic electronic search of the PubMed database to compile relevant literature, employing the following search terms: Microglia, neuroinflammation, neurodegenerative diseases, PD, AD, MS, MSA, ALS, FTD, PSP, CBD, LBD, HD, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), regulatory factors, pattern recognition receptors (PRRs), SYK, STING, Syt11, transient receptor potential vanilloid 1 (TRPV1), parthanatos, cuproptosis, disulfidptosis, ferroptosis, and lysosomal acidification. Numerous combinations of the terms were adopted to safeguard the complete coverage of the literature. First, our research assessed the association of titles and abstracts regarding this research focus. Then, the research reviewed the pertinent articles to confirm their discussion of regulatory factors associated with inflammation and novel forms of cell death linked to microglial activity. Studies that explicitly examined the relationship between regulatory factors and microglia in PD and those investigating novel forms of cell death related to microglia were selected for inclusion in our review. Publications without reaching these criteria were removed. Notably, most included literature (about 83% of the total articles) were published from 2019 to 2024.

Dysfunction of Microglia in Neurodegenerative Diseases

Microglia play an important role in immune regulation within the CNS. They exhibit morphological similarities to macrophages and primarily serve to monitor and respond to pathological alterations in the neural environment, actively identifying and clearing pathogens, abnormal cells, and metabolic waste within the CNS (Andoh and Koyama, 2021). Through dendritic-like processes, microglia extend throughout neural tissue, conducting continuous immune surveillance. When encountering pathogens or injury, they can rapidly activate and initiate an immune response to protect the nervous system from external threats (Wright-Jin and Gutmann, 2019). In the event of neural injury, microglia rapidly depolarize and migrate to the affected area, releasing cytokines and chemical mediators to boost cellular debris elimination and support the repair process. Additionally, they are critical players in modulating the inflammatory reaction during this process, thereby preventing excessive damage. Microglia also play a key role in synaptic pruning during brain development. This process is crucial for the normal development of neural networks by helping to eliminate unnecessary synaptic connections, optimize neural circuit formation, and sustain the nervous system’s plasticity. Microglia execute these important pruning functions by interacting with synapses through their processes, thereby promoting the healthy development of the nervous system (Cao et al., 2021).

With aging, microglia frequently exhibit a sustained state of ‘overactivation,’ leading to low-level chronic inflammation. Microglia continuously release cytokines during aging, like tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Although these inflammatory responses are relatively mild, their sustained presence can result in cumulative damage to the nervous system over time (Liu et al., 2022b). Chronic inflammation is a major triggering factor for neurodegenerative diseases. As individuals age, the microglial function changes, leading to abnormal responses to neural injury. The overactivation of microglia, coupled with the persistent inflammatory response they initiate, can result in neuroinflammation dysregulation, which facilitates the development of neurodegenerative disorders (Gao et al., 2023). The occurrence of neurodegenerative disorders, such as AD and PD, is closely linked with abnormal microglial activity during the aging process. Aging microglia not only demonstrate functional degeneration but may also exhibit metabolic abnormalities. These changes impair their capacity to clear metabolic waste, maintain synaptic pruning, and support neural repair. Over time, the deterioration of these functions results in a gradual decline of the nervous system, subsequently affecting neural health and cognitive function (Bartels et al., 2020). While microglia are important for immune surveillance, neural repair, and synaptic pruning within a healthy brain, as they age, their functions may become disrupted, resulting in chronic inflammation and an elevated risk of neurodegenerative diseases.

Microglial polarization, a crucial aspect of microglial functionality, is generally categorized into two primary states: M1 and M2. M1 microglia initiate and maintain local inflammatory reactions by secreting pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and reactive oxygen species (ROS) (Zhang et al., 2021; Yang et al., 2025). Persistent M1 microglia activation is a major contributor to pathological neuroinflammation. M1 microglia enhance the inflammatory reaction and may also release neurotoxic substances, such as nitric oxide (NO), which can harm neurons and induce neuronal cell death. In PD, the aggregation of α-synuclein (α-Syn) triggers the activation of microglial cells that can release a range of pro-inflammatory mediators, ultimately leading to localized inflammatory responses (Tansey et al., 2022). In contrast, when microglial cells are placed in environments with IL-4, IL-10, transforming growth factor (TGF)-β, or glucocorticoids, they can differentiate into cells of the M2 anti-inflammatory phenotype, which inhibit inflammation, boost tissue repair, and release anti-inflammatory factors (Zhang et al., 2021). During the early phases of neurodegenerative diseases, M2 microglia play a protective role by facilitating damage repair, clearing cellular debris, and promoting neurogenesis. However, as the disease progresses, particularly during the chronic stage, M2 microglia functionality may become compromised, resulting in an inability to effectively suppress ongoing inflammation, which impedes the neural repair process (Leng and Edison, 2021). The imbalance between M1 and M2 polarization is an important factor in the development of numerous neurodegenerative disorders (Tang and Le, 2016). For instance, in AD, M1 microglia activation is closely linked to amyloid plaque accumulation, whereas the dysfunction of M2 microglia hinders the repair of affected regions (Leng and Edison, 2021).

Furthermore, an individual’s genetic background considerably influences microglial dysfunction and excessive activation. Specific gene mutations, such as those affecting the receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE), can modify microglial function in neurodegenerative disorders, leading to excessive activation or dysfunction (McQuade et al., 2020). During the aging process, microglial functionality progressively diminishes. Notably, the reactivity of these cells markedly increases, leading to excessive activation. This overactivation causes microglia to respond to damage with heightened aggression, resulting in chronic inflammation and neuronal damage within the nervous system (Bartels et al., 2020). Abnormally folded proteins, such as α-Syn and amyloid-beta peptide (Aβ), along with environmental factors such as pesticides and air pollutants, can rapidly activate microglia in response to potential neural injury (Merighi et al., 2022), chronic psychological stress, or low-grade infections. Other factors, including metabolic dysregulation, oxidative stress, and mitochondrial dysfunction, also considerably impact microglial function. Oxidative stress, by inducing microglial activation, promotes the secretion of additional pro-inflammatory factors, thereby exacerbating the neuroinflammatory response (Li et al., 2022b). Although microglia endeavor to clear these abnormal proteins, their excessive activation frequently results in more severe neuronal damage. Overall, microglial dysfunction occurring during normal physiological states and with aging is a critical factor in nervous system immunity.

While moderate microglial activation assists in the clearance of cellular damage and pathogens, excessive activation can result in an overproduction of inflammatory mediators, exacerbating neural damage. Overactivation is strongly associated with chronic inflammatory responses and serves as the pathological basis of many neurodegenerative diseases.

New Types of Cell Death in Microglia

With the development of cell biology and molecular medicine has come a gradual realization that the intricacy of cell death cannot be wholly explained by its traditional forms, like apoptosis (Kerr et al., 1972) and necrosis. Microglia have been discovered to play a crucial role in diverse pathological conditions such as neuroinflammation, neurodegenerative diseases, and brain injury. Emerging forms of cell death, like parthanatos, ferroptosis, cuproptosis, and disulfidptosis, have become new research hotspots regarding their role in microglia and neurodegenerative diseases. “New types of cell death” is a broad concept encompassing various cell types, and we primarily focus on their roles in neurodegenerative diseases. This term refers to a class of non-classical cell death mechanisms that diverge from the traditional pathways of apoptosis and necrosis. These forms of cell death are prevalent in the nervous system and are particularly relevant to research concerning neurodegenerative diseases like PD and AD. Although the function of microglia in neuroinflammation and neurodegenerative disorders has been explored extensively, research on new types of cell death is not confined to microglia alone. These new forms also considerably influence the cell death mechanisms of other brain cells, including neurons, astrocytes, and oligodendrocytes. In this context, our research emphasizes microglia’s new cell death types.

In microglia, ferroptosis is typically characteristic of iron ion accumulation and the overproduction of lipid peroxides. This form of cell death is considerably associated with pathological conditions, including neurodegenerative disorders and ischemic brain injuries. In PD, cuproptosis might be conducive to heightened oxidative stress in the local environment by disrupting the microglial metabolic functions, thereby promoting disease progression (Tang et al., 2022). Disulfidptosis serves as an important player in neuroinflammatory disorders like multiple sclerosis (MS) and AD. In microglia, disulfidptosis frequently relates to the secretion of inflammatory factors, which can exacerbate local neuroinflammatory responses. The activation of parthanatos in microglia is closely related to oxidative stress, DNA damage, and neurodegenerative changes (Zheng et al., 2022). However, as the disease progresses, the activation of cell death mechanisms like ferroptosis and disulfidptosis may further deteriorate microglial function, resulting in an overactive neuroinflammatory response that impairs neuronal survival.

Microglia and ferroptosis

The interplay between microglial ferroptosis and neuroinflammation is garnering increasing attention within the academic community (Dixon et al., 2012), with extant evidence elucidating the precise correlation between the two processes (Liu et al., 2022a). Ferroptosis, recognized as a novel form of cellular demise, is predominantly characterized by ferrous ion accumulation within cells, the peroxidation of lipids, and an increase in ROS, concomitant with a disruption in cellular antioxidant homeostasis (Yu et al., 2021; Feng et al., 2024). Together, these alterations drive cells toward death.

Extracellular iron (Fe 3+ ) binds to transferrin and is internalized via endocytosis mediated by transferrin receptor 1, leading to the formation of an endosome. Within the endosome’s acidic environment, metal reductases such as Steap3 convert iron (Fe 3+ ) into the more bioavailable iron (Fe 2+ ). Iron (Fe 2+ ) is then transported to the cytoplasm through divalent metal transporter 1 and enters the labile iron pool. Under pathological conditions, excessive iron (Fe 2+ ) accumulation in the labile iron pool triggers the Fenton reaction, producing a considerable quantity of ROS. These ROS engage in a peroxidation response to polyunsaturated fatty acids (PUFAs) on the cell membrane and the PUFA-coenzyme A then forms. This crucial step is catalyzed by long-chain acyl-coenzyme A synthetase 4 (ACSL4). Subsequently, lysophosphatidylcholine acyltransferase 3 esterifies PUFA-coenzyme A into phosphatidylethanolamines. Lipoxygenases ultimately oxidize this phosphatidylethanolamine into lipid peroxides, initiating ferroptosis (Dixon et al., 2012). The antioxidant system, called system Xc – , comprises two subunits: solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2). System Xc – maintains intracellular glutathione (GSH) levels by regulating cystine uptake, which is essential for scavenging ROS and inhibiting ferroptosis. GSH is an important reducing cofactor for glutathione peroxidase 4 (GPX4). Compromised GSH synthesis leads to diminished GPX4 activity, which results in lipid peroxide accumulating within the cell, ultimately triggering ferroptosis ( Figure 1 ).

Crosstalk between ferroptosis and disulfidoptosis in microglia.

Ferroptosis can be induced through three interrelated pathways. Firstly, Fe 3+ binds to TF and enters the cell via TFR1, where it is reduced to Fe 2+ by Steap3 in the endosome and released into the LIP through DMT1. Excess Fe 2+ can trigger the Fenton reaction, leading to increase ROS and lipid peroxidation. SEC24B may inhibit ferroptosis by suppressing DMT1. Secondly, ROS reacts with PUFAs on the cell membrane, catalyzed by ACSL4 to form PUFA-CoA, which LPCAT3 esterifies into PEs that are oxidized to lipid peroxidation by 15-LOX. Thirdly, system Xc – is made up of two components: SLC7A11 and SLC3A2. Cystine is converted to cysteine at the expense of NADPH. L-OOH is converted to L-OH under the mediation of GPX4. Under oxidative stress, Keap1 changes conformation, releasing Nrf2 into the nucleus, where it binds to ARE and promotes GPX4 expression. Ferroptosis related to disulfidoptosis involves the SLC7A11 subunit in system Xc-. High SLC7A11 expression during glucose starvation converts cystine to cysteine, depleting NADPH and causing disulfide bond accumulation in F-actin, ultimately triggering disulfidoptosis. Glucose inhibitors can exacerbate disulfidoptosis by inhibiting GLUT. 15-LOX: 15-Lipoxygenase; ACSL4: long-chain acyl-CoA synthetase family member 4; ARE: antioxidant response elements; DMT1: divalent metal transporter 1; GLUT: glucose transporters; GPX4: glutathione peroxidase 4; GSH: glutathione; LIP: labile iron pool; L-OH: lipid alcohols; L-OOH: lipid hydroperoxides; Nrf2: nuclear factor erythroid 2-related factor 2; PEs: phosphatidylethanolamines; PUFAs: polyunsaturated fatty acids; ROS: reactive oxygen species; SEC24B: secretory pathway component 24B; TF: transferrin; TFR1: transferrin receptor 1.

When microglia are exposed to iron, a rise in inflammatory factors—including IL-8—is observed, suggesting that excess iron may induce an inflammatory response within microglia. This response results in increased divalent metal transporter 1 and decreased ferroportin 1, accompanied by a notable increase in ferritin expression. These changes further exacerbate the accumulation of intracellular iron ions (Liu et al., 2022a). In studies employing PD mouse models, manifestations and hallmarks of ferroptosis are particularly pronounced. Strategies designed to ameliorate ferroptosis demonstrate substantial neuroprotective benefits for dopaminergic neurons and significantly enhance the recovery of motor functions in mice (Mahoney-Sánchez et al., 2021). Upon stimulation with lipopolysaccharide (LPS), ACSL4 expression is upregulated, facilitating the synthesis of inflammatory cytokines by upregulating vestigial-like family member 4 and activating the nuclear factor kappa B (NF-κB) signaling pathway (Zhou et al., 2023). ACSL4, an emerging regulator within the PUFA metabolic pathway, regulates vestigial-like family member 4 expression and promotes ferroptosis in microglia by affecting lipid metabolism, thereby mediating the occurrence of neuroinflammation (Zhou et al., 2023). Regulating ACSL4 activity or its effects on lipid metabolism may help control neuroinflammation and protect neuronal cells. Because M2 microglia exhibit higher sensitivity to ferroptosis, strategies to inhibit ferroptosis may help mitigate neuroinflammation (Yu et al., 2023).

Recent applications of genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening technology have effectively identified a crucial regulatory factor influencing the ferroptosis process in microglia—the vesicular transport gene secretory pathway component 24B (SEC24B) (Ryan et al., 2023). SEC24B functions as a regulatory protein that cooperates with coat protein complex II (COPII) to enhance the efficient transport of proteins from the endoplasmic reticulum to Golgi apparatus. Scharaw et al. (2016) demonstrated that epidermal growth factor increases the number of endoplasmic reticulum export sites rich in SEC24B through a process dependent on transcription ring finger protein 11, thereby regulating the trafficking rate of epidermal growth factor receptor. Activation of the epidermal growth factor receptor signaling pathway may augment the cell’s antioxidant capacity, thus reducing the incidence of ferroptosis. Furthermore, studies have shown that regulatory systems composed of splice variants of the endocytosis regulator bone morphogenetic protein 2 kinases can modulate the autophagy process by regulating the assembly of SEC24B-positive COPII vesicles (Cendrowski and Miaczynska, 2020). SEC24B engages in the formation of autophagosomes within the endoplasmic reticulum–Golgi intermediate chamber, a process that is particularly crucial for ferritin degradation, which releases a considerable amount of iron (Fe 2+ ) into the labile iron pool, promoting iron-dependent ferroptosis (Ryan et al., 2023). Notably, microglia with knockout of the SEC24B gene exhibit high resistance to ferroptosis and a significant reduction in ferroptotic events. This finding illustrates SEC24B’s potent regulatory role in inducing ferroptosis in microglia. SEC24B may exert its effects by directly modulating the expression levels and functions of iron regulatory or transport proteins. It may also regulate iron levels through indirect pathways, such as by influencing cell signaling pathways or gene expression (Ryan et al., 2023). These findings significantly enhance our understanding of the function of microglia in neurodegenerative diseases.

Nuclear factor E2-related factor 2 (Nrf2) works as an essential gene modulator with high sensitivity to oxidative stress and plays a vital role in regulating pathways associated with ferroptosis (Lane et al., 2021). Nrf2 is an essential gene regulator with high sensitivity to oxidative stress, which makes it an important player in regulating pathways associated with ferroptosis (Lane et al., 2021). Under normal cellular homeostasis, Nrf2 binds to the Keap1 protein at the periphery of the nucleus, maintaining an inactive state. When exposed to oxidative stress, Keap1 undergoes a conformational change, allowing Nrf2 to transfer to the nucleus and interact with antioxidant response elements. This mechanism activates several antioxidant genes, including GPX4 and ferritin heavy chain 1, preventing the onset of ferroptosis. In microglia, Ras selective lethal 3 (RSL3) suppresses LPS-induced inflammatory reaction by promoting Nrf2 protein expression. Traditionally, RSL3 is believed to exert its effects by inhibiting the RNA polymerase II integrated into the transcription initiation sites of pro-inflammatory cytokine genes, leading to decreased transcription. RSL3’s induction of ferroptosis is typically associated with its impact on intracellular ROS levels. Inhibiting GPX4 prevents cells from effectively eliminating lipid peroxides, leading to iron-dependent cell death (Cui et al., 2021). RSL3’s dual mechanism of action provides new insights into its potential applications in neurodegenerative diseases. On the one hand, by inhibiting the inflammatory response, RSL3 may help alleviate neuroinflammation; on the other hand, its ability to induce ferroptosis must be carefully considered to avoid harming healthy cells. In dopamine and iron-treated PC12 cells, dopamine peroxide was found to cause GPX4 degradation via the neural precursor cell expressed in the developmentally downregulated 4 (NEDD4)-mediated ubiquitin-proteasome pathway, inducing lipid peroxide accumulation within cells and heightened oxidative stress and potentially boosting the occurrence of ferroptosis (Sun et al., 2023). NEDD4, which encodes an E3 ubiquitin ligase, plays a role in protein degradation and signal transduction mechanisms. Investigating the regulatory mechanisms of GPX4 and the potential role of NEDD4 in modulating antioxidant responses may help with the development of strategies to protect dopaminergic neurons and alleviate neuroinflammation.

Research on the regulatory mechanisms governing ferroptosis in microglia and how these factors could be strategically manipulated to inhibit ferroptosis may unveil novel avenues for preventing and treating the neuroinflammatory responses implicated in neurodegenerative disorders. Targeted therapeutic interventions aimed at the Nrf2 pathway and the identification of ferroptosis inhibitors are anticipated to open new frontiers in mitigating chronic neuroinflammation and decelerating neurodegenerative processes.

Microglia and cuproptosis

Cuproptosis, a recently identified form of cell death, has been correlated with disruptions in copper metabolism (Tsvetkov et al., 2022). Because microglia, as crucial players, regulate neuronal survival by modulating copper ion levels and distribution, cuproptosis may be implicated in microglial activation and subsequent neuroinflammatory responses in neurodegenerative diseases (Tang et al., 2022).

Copper exists in two primary forms within the body—Cu 2+ and Cu + —both of which are essential for various cellular processes. Extracellular Cu 2+ is reduced to Cu + by membrane-bound metalloreductases and transported into the cell via copper transporter 1 (CTR1). Within the cell, Cu + can bind to copper chaperone proteins such as antioxidant 1, cytochrome c oxidase copper chaperone COX17, and copper chaperone for superoxide dismutase, facilitating transport to target proteins (Xu et al., 2013). To maintain homeostasis, excess copper ions are exported to the extracellular space by copper pumps (ATP7A/B). Excessive copper can directly bind to acetylated proteins during tricarboxylic acid circulation, causing ferredoxin 1-mediated protein clustering and disruption of Fe-S cluster proteins, ultimately leading to cell death (Chen et al., 2022).

Additionally, copper accumulation can disrupt Fe-S cofactors, which trigger the Fenton reaction, generate ROS, and thereby induce lipid peroxidation and oxidative stress. Microglia regulate copper transporter-related gene expression through transcriptional modulation by transcription factors. Inflammatory conditions alter the expression of copper transporters, such as CTR1 and ATP7A, disrupting copper homeostasis via NF-κB activation (Chen et al., 2022). Under oxidative stress, Nrf2 also upregulates copper transporter expression to mitigate oxidative damage.

Elevated copper consumption and increased environmental copper levels are major risk factors for PD (Huang et al., 2024), and aging-related disturbances in copper homeostasis may also contribute to PD and other neurodegenerative disorders (Zhong et al., 2024a). α-Syn inclusion formation is promoted by increased CTR1 expression in yeast cells expressing α-Syn (Gou et al., 2021). In CTR1-deficient mouse models, α-Syn phosphorylation at S-129 is markedly reduced, suggesting a critical role for copper ions in α-Syn aggregation and PD pathogenesis (Gou et al., 2021). Our research indicates that lipid metabolism abnormalities can disrupt intracellular copper balance, thereby promoting cuproptosis. Cuproptosis is also exacerbated by the lipid metabolism dysregulation exhibited by activated microglia in PD. Additionally, ferredoxin 1 gene regulation in the acetylation process of tricarboxylic acid circulation is crucial for cuproptosis (Zhong et al., 2024b). Furthermore, our team posits that ferredoxin 1 directly triggers cuproptosis via modulating copper ion valence while enhancing ferroptosis sensitivity by mediating GPX4 degradation (Song et al., 2025). High glucose conditions may induce copper deposition in microglia in vitro , which is associated with the abnormal expression of signal transducer and activator of transcription 1 (STAT1) in SLC31A1 (Hu et al., 2024). Cuproptosis in microglial cells may be pivotal in neurodegenerative disease pathogenesis, but elucidation of the underlying mechanisms remains incomplete ( Table 1 ).

Table 1 Comparison of ferroptosis and cuproptosis Ferroptosis Cuproptosis Condition Ferrous ion accumulation Copper ion accumulation Feature Membrane lipid peroxidation Acylated protein accumulation ROS↑ Fe-S cluster protein ↓ Imbalance of the antioxidant system Key biomarker GPX4↓ ATP7A/B↓ MDA↓ FDX1↓ GSH↑ SLC31A1↑ ACSL4↑ Related disease Neurodegenerative diseases Neurodegenerative diseases Ischemia-reperfusion injury Cardiovascular disease Tumor Tumor Wilson’s disease ACSL4: Long-chain acyl-CoA synthetase family member 4; FDX1: ferredoxin 1; GPX4: glutathione peroxidase 4; GSH: glutathione; MDA: malondialdehyde; ROS: reactive oxygen species; SLC31A1: solute carrier family 31 member 1.

Comparison of ferroptosis and cuproptosis

ACSL4: Long-chain acyl-CoA synthetase family member 4; FDX1: ferredoxin 1; GPX4: glutathione peroxidase 4; GSH: glutathione; MDA: malondialdehyde; ROS: reactive oxygen species; SLC31A1: solute carrier family 31 member 1.

Microglia and disulfidptosis

Disulfidptosis is distinct from alternative cellular death mechanisms and is characterized by the intracellular buildup of disulfide bonds, which causes the degradation of cytoskeletal proteins and F-actin (Liu et al., 2023c; Li et al., 2024). SLC7A11, a cystine/glutamate reverse transporter, is vital for transporting amino acids across the cell membrane. The SLC7A11 gene, an important modulator of disulfidptosis and ferroptosis, is significantly downregulated in PD, protecting dopaminergic neurons by activating the transsulfuration pathway (Vallerga et al., 2020; Xiao et al., 2024). Cellular cystine is reduced to cysteine via nicotinamide adenine dinucleotide phosphate (NADPH), and cysteine is essential for cellular functions. NADPH synthesis is restricted when there is insufficient glucose supply, leading to the accumulation of disulfide bonds and triggering cellular death (Zheng et al., 2023b). The Ras-related C3 botulinum toxin substrate 1 (Rac1)-wave regulatory complex pathway is important in this process. Overexpression of Rac1 causes activation of the non-catalytic clathrin-associated protein (NCK)-associated protein 1, which then interacts with other subunits to form the Wave regulatory complex, facilitating the development of lamellipodia and disulfidptosis (Ding et al., 2022). Lamellipodia may be a key target for disulfide bond stress (Liu et al., 2023c; Chen et al., 2024).

The metabolic activities of microglia, including the supply of glucose and NADPH, are essential for their function. Tumor cell growth in renal cancer can be inhibited by reducing cancer cells’ glucose uptake via glucose transporter inhibitors; however, this effect may be modulated by the SLC7A11 expression level (Zheng et al., 2023a). This suggests that glucose starvation and high SLC7A11 expression may synergistically increase cellular vulnerability to oxidative stress, thereby inducing disulfidptosis. Cell death resulting from glucose starvation is characterized by elevated SLC7A11 levels and can trigger the accumulation of aberrant disulfide bonds and the breakdown of F-actin (Liu et al., 2023c). Disulfide bonds are a type of post-translational modification of proteins. The underlying influence on disulfidptosis of other post-translational modifications—like ubiquitination and glycosylation of GPX—warrants further investigation (Wang et al., 2024). The regulators involved in disulfidptosis may considerably affect microglia, and inhibitors could potentially delay the progression of PD.

Microglia and parthanatos

Parthanatos, as a form of cell death, relates to the activation of poly(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), and is characterized by the overactivation of PARP-1, the accumulation of poly(ADP-ribose) polymers, mitochondrial dysfunction, and the translocation of apoptosis-inducing factor (AIF) into the nucleus (Andrabi et al., 2008; Wang et al., 2016). Upon considerable DNA damage, PARP-1 is hyperactivated, leading to poly (ADP-ribose) migration from the nucleus to the mitochondria, initiating AIF secretion (Wang et al., 2011b). The nuclear translocation of AIF is facilitated by interacting with macrophage migration inhibitory factor in the cytoplasm, ultimately resulting in cell death (Zheng et al., 2022). Increased activation and nuclear translocation of AIF have been observed among patients with PD (Fricker et al., 2018; Li et al., 2022a). Microglia may influence the parthanatos process by modulating PARP-1 activity and responding to oxidative stress. In PD, hyperactive PARP-1 could contribute to impairing blood–brain barrier (BBB) functionality, potentially exacerbating the patient’s state of illness (Li et al., 2022a). PARP-1 inhibitors may help to mitigate neuronal damage, potentially slowing PD progression and offering a novel therapeutic strategy for its treatment ( Figure 2 ).

The occurrence mechanism of parthanatos in microglia.

DNA damage triggers the excessive activation of PARP-1. Upon activation, PARP-1 synthesizes PAR, which subsequently translocates from the nucleus to the mitochondria, resulting in the release of AIF from the mitochondria. AIF then combines with MIF in the cytoplasm and translocates to the nucleus, where it interacts with nuclear DNA, ultimately leading to cell death. Furthermore, α-Syn PFF can also enter the cell and induce DNA damage. AIF: Apoptosis-inducing factor; MIF: macrophage migration inhibitory factor; PAR: poly(ADP-ribose); PARP-1: poly(ADP-ribose) polymerase 1; α-Syn PFF: preformed fibrils of α-synuclein.

Microglia Membrane Receptors Mediate Neuroinflammatory Responses

Pattern recognition receptors (PRRs) constitute the foundation of microglial immune functions and are extensively expressed on the plasma membrane of microglia (Lind-Holm Mogensen et al., 2023). Microglia are activated by PRRs that identify either pathogen- or damage-related molecular modes through their specific ligand interactions, thereby regulating the synthesis of inflammatory mediators, cytokines, cellular surface molecules, and growth factors (Li and Wu, 2021; Gao et al., 2023). These receptors include, but are not limited to, Toll-like receptors (TLRs), purinergic receptors (P2X and P2Y), NOD-like receptors (NLRs), the C–X–C chemokine receptor family, and clusters of differentiation 14 (CD14) and differentiation 36 (CD36) (Heidari et al., 2022). TRPV1, an ion channel, can be modulated by signaling pathways activated by PRRs during the inflammatory process. Through PRRs, damaged signals or pathogens trigger the secretion of inflammatory agents such as cytokines and prostaglandins (Xiao et al., 2022). These mediators can directly activate TRPV1, thereby enhancing nociception. In addition to transducing pain signals in sensory neurons, TRPV1 is a key player in microglial cells. Other than the receptors described above, the CD200/CD200R system, comprising a cluster of differentiation (CD)200 and its receptor (CD200R), also contributes to microglial regulation. CD200R helps maintain the quiescent state of microglia by integrating into CD200, thus inhibiting excessive immune responses (Najar et al., 2012).

Toll-like receptors

TLRs are abundantly expressed on microglial surfaces, enabling them to detect external and internal signals, thereby considerably contributing to the initiation of neuroinflammation (Li and Wu, 2021; Wang et al., 2025). TLR activation generally coincides with the stimulated downstream signaling pathways, encompassing mitogen-activated protein kinase and NF-κB, which subsequently enhance the expression and secretion of inflammatory mediators. TLR expression on microglia is significantly elevated in samples from patients with PD, and this upregulation is closely associated with excessive neuroinflammation and neurodegenerative changes in the affected areas (Heidari et al., 2022). To date, 13 types of TLRs have been identified in humans, ranging from TLR1 to TLR13 (Yan et al., 2014). Pathological α-Syn can bind to specific TLRs on the microglial surface, particularly TLR2 and TLR4. This engagement activates the NF-κB signaling pathway while boosting the formation of the NLRP3 inflammasome, which produces inflammatory mediators and ROS (Kouli et al., 2019; Li et al., 2021b). In a mouse model featuring the alanine-to-threonine substitution at position 53 (A53T), the absence of the TLR2 gene diminished the interaction with the downstream protein myeloid differentiation primary response 88 (MyD88), thereby impairing the stimulated NF-κB signaling pathway. This ultimately reduced neuroinflammation and protected neurons (Dutta et al., 2021), illustrating the vital role of the TLR2 receptor in neuroinflammation.

Additionally, the upregulation of TLR2 and TLR4 expression levels in SH-SY5Y neurons co-cultured with activated microglia may also facilitate α-Syn phosphorylation and aggregation by activating the p38 mitogen-activated protein kinase/c-Jun N-terminal kinase signaling pathway (Chung et al., 2022). Knockout of TLR7 and TLR8 in mice can prevent dopamine consumption from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine while significantly reducing α-Syn and TNF-α levels in dopaminergic neurons (Campolo et al., 2020). This highlights the regulatory role of TLRs in neurodegenerative diseases, indicating that further research on diverse TLR phenotypes and their functional mechanisms in neuroinflammation can aid in the development of novel therapeutic strategies to manage neuroinflammation.

Purinergic receptors

Adenosine triphosphate (ATP) can elicit cellular activation responses by activating P2X receptors (such as P2X4 and P2X7 purinergic receptors) and P2Y receptors (such as P2Y12 and P2Y13 purinergic receptors) expressed on microglia (Atta et al., 2023). The engagement of these receptors is pivotal for the motility and relocation of microglia, constituting a critical phase in the initiation of neuroinflammation (Gómez Morillas et al., 2021; Iring et al., 2022). P2X receptors function as ligand-gated ion channels, which are essential for the rapid influx of calcium ions. The stimulation of P2X7 results in calcium ion entry, prompting the formation of pores by P2X7 and pannexin-1 in cell membranes. This contributes to boosting the secretion of additional ATP into the extracellular environment, thereby enhancing inflammatory mediator expression (Rotondo et al., 2022). The application of inhibitors for P2X4 and P2X7 within rat microglia resulted in an obvious decline in TNF-α expression, indicating that P2X receptors regulate the inflammatory reaction (Imraish et al., 2023). By impeding P2X7 receptor viability, the excessive activation of microglia can be alleviated, inflammation can be suppressed, and neurological function in animal models can be improved to some extent (Kim et al., 2020; Zheng et al., 2024). P2Y receptors are G protein-coupled receptors that respond to ADP and are important in the modulation of intracellular signaling processes. P2Y12 is particularly significant in the context of neuroinflammation. In their mouse model of PD triggered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, András Iring and colleagues discovered that the immunoreactivity of P2Y12 co-localized with CD68 within the substantia nigra. This finding implies a strong association between P2Y12 and the activated microglia in specific PD-related brain areas (Iring et al., 2022). In vivo blockade of P2Y12 activation can effectively inhibit microglial activation, thereby impeding disease progression. Inhibiting P2Y12 signaling results in decreased microglial mobility, potentially affecting the clearance and repair processes in inflamed regions (Chinnathambi and Das, 2023). This research provides novel insights into the mechanisms underlying cell migration during neuroinflammatory responses. Previous studies on these receptors suggest that modulating their activity may help mitigate neuroinflammation and protect neurons. Identifying effective compounds that regulate the activity of these receptors can prompt progress in the development of novel therapeutic strategies to mitigate neurodegenerative disorders.

NOD-like receptors

The NLR family comprises 22 receptors across five primary classes that are ubiquitously present in human cells (Liu and Sun, 2012). NLRP3 and NLRC5 are two subtypes found in microglia, playing major roles in neuroinflammation. Pathophysiological factors, including oxidative stress, mitochondrial dysfunction, and impaired mitophagy, substantially contribute to the activation of the NLRP3 inflammasome complex. Inhibiting the NLRP3 inflammasome can attenuate the inflammatory reaction (Cheng et al., 2024), reduce the aberrant aggregation of α-Syn, and mitigate injury to dopaminergic neurons, thereby ameliorating motor symptoms in PD mouse models (Li et al., 2021b). Han et al. (2019) demonstrated that the small molecule kaempferol induces microglial autophagy within a PD mouse model, leading to reduced NLRP3 protein expression, inactivation of the NLRP3 inflammasome, and decreased secretion of IL-1β. Additionally, Ahmed et al. (2021) suggested that celastrol, which promotes Parkin-dependent mitophagy, inhibits NLRP3 activation in microglia of the substantia nigra pars compacta region in mice, thereby restoring ATP levels, conferring neuroprotective effects, and improving behavioral parameters. Heat shock protein 90 inhibitors reduce inflammatory responses by accelerating Parkin-induced degradation of NLRP3; Parkin regulates NLRP3 inflammasome activation in microglia via polyubiquitination, potentially mitigating PD-associated neurodegeneration (Yan et al., 2023). These findings suggest that modulating NLRP3 inflammasome function within microglia may become a prospective therapeutic approach to PD. Increased NLRC5 expression was observed in neurons and microglia of the substantia nigra and striatum in PD mouse models triggered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and various toxins. Conversely, PD mice lacking NLRC5 exhibited reduced expression of pro-inflammatory genes within primary microglia and astrocytes, likely due to suppressing NF-κB and mitogen-activated protein kinase signaling pathway activation. Elucidating the regulatory roles of NLRC3 and NLRC5 in inflammatory signaling pathways might offer promising avenues for the exploration of new therapeutic strategies to mitigate neuroinflammation.

C–X–C chemokine receptors

The C–X–C chemokine receptor (CXCR) family of chemokine receptors plays a pivotal role in neuroimmune regulation by precisely modulating microglial activity and function through interactions with various ligands, including C–X–C motif chemokine ligand 12 (CXCL12). CXCL12’s interaction with its receptor CXCR4 considerably influences neuronal migration, synapse formation, and neural circuit establishment. Furthermore, the presence and localization of CXCL12 and its receptor within the nervous system are intricately linked to neurodegenerative alterations, with disruptions in the CXCL12/CXCR4 signaling pathway potentially affecting neuronal survival and function (Yan et al., 2022). Reducing CXCR5 expression in LPS-induced primary microglia can attenuate neuroinflammation by impeding the NF-κB/STAT3 signaling pathway (Shen et al., 2021). Investigating the mechanisms of CXCR receptor family members and their ligands in microglia can enhance our understanding of their impact on neuroinflammation and neurodegenerative changes.

Cluster of differentiation 14 and cluster of differentiation 36

CD14, a cell surface antigen as a co-receptor for TLRs, triggers innate immune reactions in macrophages and monocytes against pathogens and tissue injury. CD14 participates in the inflammatory response by binding to lipid peroxides and damage-related molecular modes. It facilitates the transfer of LPS to the TLR2-myeloid differentiation protein 2 complex, enhancing interactions between TLRs and adaptor proteins, such as MyD88, TRIF (TIR-domain-containing adapter-inducing interferon-β), and TRAM (TRIF-related adaptor molecule), which initiate intracellular signaling (Sharygin et al., 2023). Protosappanin A inhibits the IκB kinase/inhibitor of the κB protein/NF-κB inflammatory signaling pathway by interfering with CD14-TLR4 interactions in LPS-induced BV-2 microglia, effectively reducing oxidative stress and neuroinflammation (Zeng et al., 2012). CD36, a member of the class B scavenger receptor family, functions as a multi-ligand pattern receptor, facilitating microglial responses to oxidative stress, inflammation, and mitochondrial dysfunction. IL-10 modulates CD36 expression and function, influencing microglial phagocytic behavior and inflammatory responses (Li et al., 2021a). Elucidating the interaction between CD36 and IL-10 in microglial cells could reveal novel molecular targets for preventing and treating neurodegenerative disorders. The CD36 binding to nanoparticles can interact with CD36 expressed on BV-2 microglia, preventing the aggregation of extracellular α-Syn, reducing the activated inflammatory signaling pathways like NF-κB, lowering pro-inflammatory mediator levels, and enhancing anti-inflammatory cytokine synthesis (e.g., TGF-β), thereby exerting an anti-inflammatory effect that may slow neurodegenerative disease progression (Zhao et al., 2022b).

Transient receptor potential vanilloid 1

TRPV1 is an innovative ion channel predominantly expressed in sensory neurons that facilitates cation influx, particularly calcium ions (Ca 2+ ) (Xiao et al., 2022). TRPV1 receptor expression is remarkably escalated in the striatum of mice with PD (Maximiano et al., 2024). Yuan et al. (2022) employed photothermal nanomaterials to regulate the activation of TRPV1 channels on the microglial membrane, inducing Ca 2+ influx and activating the autophagy-associated protein 5 and the Ca 2+ /calmodulin-dependent protein kinase kinase 2/AMP-activated protein kinase/mechanistic target of rapamycin signaling pathways. This process enhanced α-Syn clearance and degradation, improving PD treatment efficacy and significantly enhancing the motor abilities of the model mice. The development of drugs targeting TRPV1 channels therefore holds promise for novel therapeutic strategies to ameliorate motor deficits.

Cluster of differentiation 200/cluster of differentiation 200 receptor

CD200R, an inhibitory receptor on microglia, inhibits excessive microglial activation by binding to its ligand CD200. One blocking antibody against CD200R resulted in increases in microglial activation and the expression of pro-inflammatory factors in a 6-hydroxydopamine-induced PD mouse model (Zhang et al., 2011). Reduced CD200 expression correlates with increased microglial reactivity in the substantia nigra of rodents (Wang et al., 2011a), suggesting that CD200 is pivotal in regulating microglial behavior. Additionally, Frank et al. (2018) demonstrated that CD200R expression in microglia is downregulated in the hippocampus of stressed rats, which relieves the inhibitory effect and triggers neuroinflammation, enhancing inflammatory mediator expression. These findings highlight the significance of the CD200/CD200R pathway in sustaining microglial homeostasis and modulating neuroinflammatory processes. Dysregulation within this pathway can exacerbate neuroinflammation and contribute to the progression of neurodegenerative disorders.

The engagement of these receptors is crucial in the etiology of neurodegenerative disorders. Integrating specific membrane receptors can elucidate the neuroinflammatory mechanisms, providing novel insights and targets for therapeutic intervention.

Lysosomal Acidification in Microglia

Lysosomal acidification and autophagic clearance in microglia preserve neuronal health in neurodegenerative diseases. Lysosomes, which are acidic intracellular organelles, employ V-ATPase to transport protons (H + ) into their lumen to maintain an acidic pH environment that is essential for degradation and autophagic clearance functions (Mindell, 2012). In PD, impaired lysosomal acidification can trigger aberrant protein aggregation, including α-Syn, which compromises microglial clearance of damaged organelles, exacerbating neuronal injury and neurodegeneration (Quick et al., 2023). Lactic acid, a crucial intercellular signaling metabolite, enhances lysosomal acidification in microglia via the monocarboxylate transporter 4, which is vital for maintaining normal phagocytic function. Deficient phagocytic activity has been observed in microglia from monocarboxylate transporter 4 knockout mice (Monsorno et al., 2023). Modulating lactic acid levels or monocarboxylate transporter 4 activity may regulate microglial activation and, thus, influence neuroinflammation and neurodegenerative disease progression. Dysfunction in the autophagy–lysosomal clearance mechanism can result in pathological proteins being expelled through extracellular vesicles, which, upon uptake by other cells, can trigger immune responses, exacerbate neurodegenerative pathologies, and spread throughout the brain (Brites and Fernandes, 2015).

Currently, research on the lysosomal acidification function of microglia in neurodegenerative diseases is limited. Enhancing microglial lysosomal acidification or manipulating extracellular vesicle release and uptake could reduce neuroinflammation and offer novel therapeutic strategies for treating neurodegenerative diseases.

Role of Microglia in Neurodegenerative Diseases

Parkinson’s disease

PD is the second most widespread neurodegenerative disorder after AD, with its onset risk closely associated with aging (Tolosa et al., 2021). Pathologically, PD is primarily characterized by the degradation of dopaminergic neurons within the substantia nigra, together with the aberrant accumulation of α-Syn and a progressive escalation of neuroinflammation within the CNS (Ma et al., 2024; Morris et al., 2024). Clinically, PD manifests with a spectrum of symptoms, including motor impairments such as resting tremor, bradykinesia, rigidity, and postural instability, alongside non-motor symptoms such as sleep disturbances, gastrointestinal dysfunction, hypokinesia, and depressive disorders (Koga et al., 2021; Liu et al., 2025).

Before the emergence of typical clinical symptoms in patients with PD, a prodromal phase occurs. During this phase, individuals may be asymptomatic or display various symptoms, including sleep disturbances and gastrointestinal dysfunction (Borghammer and Van Den Berge, 2019). Braak’s group introduced the well-known gut–brain model, which posits that during PD’s prodromal phase, infections or chemical exposures that induce inflammation in the olfactory system or gut may exacerbate neuroinflammation (Kim et al., 2019). Abnormal misfolded α-Syn has been identified in early intestinal lesions, prompting the hypothesis that α-Syn may propagate to the CNS by the vagus nerve, ultimately causing the loss of dopaminergic neurons and the development of PD (Sundaram and Garg, 2019). Misfolded α-Syn, which forms within cells, can spread to neighboring neurons and activate microglial cells, thereby exacerbating PD-associated neuroinflammation.

Inflammatory regulatory factors of microglia in Parkinson’s disease

The activation of PD microglia is associated with various regulatory factors that modulate neuroinflammation by influencing the microglial activation state. Key regulatory elements, including SYK, Syt11, stimulator of interferon genes (STING), and PGC-1α, are essential for the activation and phagocytic roles of PD microglia ( Table 2 ). By regulating the activity of these factors, it is possible to control the microglial activation state, reduce unnecessary inflammatory responses, and protect neurons from damage.

Table 2 Mechanisms of action of various regulatory factors in microglia Factor Activator Activation step Related activation pathway Effect SYK Abnormal protein aggregation, cell and myelin fragments TREM/DAP12 complex, recruits SYK mTOR and MAPK pathways (Mecca et al., 2018) Enhance the phagocytic ability of microglia Syt11 parkin gene mutation parkin gene mutation leads to Syt11↑ IL-6/STAT3 pathway (Du et al., 2017) Inhibit endocytosis STING Senescent cells or pathogen DNA, pathological aggregation of α-Syn (Luo et al., 2024) dsDNA binds to cGAS to produce cGAMP, and recruits STING TBK1/IRF3, IKK/NF-κB Release pro-inflammatory factors cGAMP: Cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate; cGAS: cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase; EndoA1: endophilin A1; MAPK: mitogen-activated protein kinase; mTOR: mechanistic target of rapamycin; NF-κB: nuclear factor kappa B; STING: stimulator of interferon genes; SYK: spleen tyrosine kinase; Syt11: synaptotagmin-11; TBK1/IRF3: tank-binding kinase 1/interferon regulatory factor 3; TREM/DAP12: triggering receptor expressed on myeloid cells 2/12 kDa DNAX-activating protein; α-Syn: α-synuclein.

Mechanisms of action of various regulatory factors in microglia

cGAMP: Cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate; cGAS: cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase; EndoA1: endophilin A1; MAPK: mitogen-activated protein kinase; mTOR: mechanistic target of rapamycin; NF-κB: nuclear factor kappa B; STING: stimulator of interferon genes; SYK: spleen tyrosine kinase; Syt11: synaptotagmin-11; TBK1/IRF3: tank-binding kinase 1/interferon regulatory factor 3; TREM/DAP12: triggering receptor expressed on myeloid cells 2/12 kDa DNAX-activating protein; α-Syn: α-synuclein.

Spleen tyrosine kinase

SYK is an important intracellular modulator of microglial activation and phagocytic function. In the context of PD, the upregulation of SYK activity correlates with an intensified microglial pro-inflammatory response. As an intracellular signaling molecule, SYK is situated downstream of receptors such as TREM2 and is essential for modulating signal transduction and effector functions, which initiate the microglial immune response (Ennerfelt et al., 2022). The TREM2 receptor, located on the surface of microglia, interacts with the adapter protein 12 kDa DNAX-activating protein (DAP12) to form a complex comprising TREM2 and DAP12, which facilitates SYK recruitment and activation. Following this activation, SYK engages with downstream signaling molecules, initiating pathways like the mechanistic target of rapamycin and the mitogen-activated protein kinase pathways, which enhance microglial phagocytic activity (Mecca et al., 2018). Additionally, signaling molecules released by microglia, such as TGF-β, play a crucial role in sustaining myelin integrity, a factor that might relate to the cognitive deficits observed in PD (Spittau et al., 2020).

Synaptotagmin-11

Syt11 has been implicated in PD pathogenesis. Genome-wide association studies have linked Syt11 genetic variants to an increased risk of PD (Ho et al., 2023). Syt11, a vesicle trafficking protein crucial for regulating vesicle fusion with plasma membranes and neurotransmitter release, inhibits microglial activation (Du et al., 2017; Zhang et al., 2023). The Syt11 gene encodes the protein Syt11, a physiological substrate for parkin, with parkin mutations leading to Syt11 accumulation in PD (Wang et al., 2018). Overexpression of Syt11 impairs microglial phagocytosis of α-Syn (Du et al., 2017), while Syt11 knockout in PD mouse models attenuates microglial overactivation (Zhang et al., 2023). Specifically, Syt11 interacts with endophilin A1, a key regulator of endocytosis, preventing excessive endocytic activity and preserving synaptic protein cycling (Wang et al., 2023). In primary microglial cells, Syt-11 knockdown (Syt-11KD) improves the release of cytokines (such as IL-6) and NO, thereby inhibiting the phagocytic activity of microglia (Du et al., 2017). It has been shown that activation of the IL-6/STAT3 inflammatory pathway improves the release of pro-inflammatory factors in inflammatory bowel disease (Nguyen et al., 2014). Therefore, we hypothesize that increased Syt-11 expression may exert its effect through the IL-6/STAT3 signaling pathway.

Stimulator of interferon genes

STING are essential signaling components in the innate immune response and are expressed in diverse cell types, including microglia (Luo et al., 2024). Activated STING can considerably alter the transcriptional state of microglial cells to modulate abnormal α-Syn accumulation. In models of idiopathic PD, the abnormal accumulation of α-Syn can activate STING, and STING knockout has been shown to ameliorate neuroinflammation and neurodegeneration (Luo et al., 2024). This suggests that elevated STING expression in PD may exacerbate the toxic influences of inflammation on the CNS.

As cells enter senescence, the activity of cyclic guanosine 5′-monophosphate-adenosine 5′-monophosphate synthase (cGAS) increases. Upon detecting cytosolic pathogens or DNA from senescent cells, cGAS rapidly catalyzes the synthesis of cyclic guanosine 5′-monophosphate-adenosine 5′-monophosphate (cGAMP). This molecule interacts with STING on the endoplasmic reticulum, leading to the activation of STING, which then recruits and motivates Tank-binding kinase 1. Tank-binding kinase 1 phosphorylates interferon regulatory factor 3, allowing it to transfer to the nucleus and initiate transcription. It also activates NF-κB, contributing to the inflammatory response by stimulating pro-inflammatory cytokine generation. Elevated cGAS expression in microglia has been shown to be associated with transcriptional changes linked to aging in a mouse model with a gain-of-function mutation in cGAS, potentially resulting in neurotoxic effects (Gulen et al., 2023). The cGAS/STING signaling pathway plays a crucial role in chronic inflammation and functional decline during aging. Gulen et al. (2023) demonstrated that the STING inhibitor H-151 can reduce the secretion of pro-inflammatory factors from aged cells in the tissue environment. Additionally, the activation of STING in microglia by STING agonists may exacerbate neuroinflammation and neurodegeneration related to the etiological accumulation of α-Syn (Hinkle et al., 2022). Inhibiting the cGAS/STING signaling pathway could represent an innovative treatment strategy to mitigate the harmful effects of chronic neuroinflammation in PD ( Figure 3 ). STING modulators, as emerging tools for immunomodulatory therapy, hold promise for treating various inflammatory diseases, with their role in regulating neuroinflammation being particularly noteworthy.

cGAS-STING signaling pathway in microglia.

Aging nuclear DNA, mitochondrial DNA, and pathogen DNA activate cGAS, which rapidly catalyzes the synthesis of cGAMP. cGAMP binds to STING on the endoplasmic reticulum, and the activated STING is transported to the Golgi via COPII, where it recruits and activates TBK1. TBK1 further phosphorylates IRF3, translocating it to the nucleus to initiate transcription. Meanwhile, activated STING also stimulates the NF-κB pathway, triggering an inflammatory response. Additionally, α-Syn PFF may cause damage to the cell nucleus, thereby activating the cGAS-STING signaling pathway. cGAMP: Cyclic guanosine 5′-monophosphate-adenosine 5’-monophosphate; cGAS: cyclic guanosine 5’-monophosphate-adenosine 5′-monophosphate synthase; ER: endoplasmic reticulum; IKK: IkB kinase; IRF3: interferon regulatory factor 3; NF-κB: nuclear factor kappa B; STING: stimulator of interferon genes; TBK1: tank-binding kinase 1; α-Syn PFF: alpha-synuclein preformed fibrils.

Peroxisome proliferator-activated receptor-γ coactivator-1α

As a coactivator, PGC-1α potentiates the transcriptional activity of nuclear receptors and is predominantly expressed in metabolically active tissues. It plays a pivotal role in coordinating transcriptional programs linked to cell energy metabolism and mitochondrial function, and its dysregulation is involved in the etiology of PD. A previous study has shown that PGC-1α upregulation can activate key transcription factors involved in mitochondrial biogenesis. The interaction between PGC-1α and the P65 subunit of NF-κB is intensified in neuroinflammatory conditions, resulting in reduced PGC-1α expression and activity (Abu Shelbayeh et al., 2023). This decrease is particularly pronounced in the bloodstreams of patients with PD, illustrating that PGC-1α levels are negatively associated with disorder severity. Upon activation, M1 microglia engage in phagocytosis and the clearance of apoptotic cell debris while concomitantly secreting pro-inflammatory cytokines. Elevated levels of these cytokines in serum and cerebrospinal fluid drive immune response progression. Conversely, in an environment enriched with IL-4, IL-10, TGF-β, or glucocorticoids, microglia can differentiate into the M2 anti-inflammatory phenotype, suppressing inflammation, promoting tissue repair, and secreting anti-inflammatory factors (Zhao et al., 2022a). In one mouse model of paclitaxel-induced cognitive impairment, resveratrol treatment activated the Sirtuin 1/PGC-1α pathway. This intervention decreased oxidative stress while elevating the concentrations of anti-inflammatory factors and simultaneously reducing the expressions of pro-inflammatory factors, thereby facilitating the polarization of microglia to the M2 phenotype (Liu et al., 2023b). This highlights the crucial role of PGC-1α in regulating microglial polarization between M1 and M2 states, which enhances its anti-inflammatory properties.

PGC-1α also promotes mitochondrial autophagy through Unc-51, including autophagy activating kinase 1 in microglia during acute ischemic stroke, which reduces NOD-like receptor family pyrin domain containing 3 (NLRP3) activation, inhibiting neuroinflammation and protecting neurons (Han et al., 2021). Thus, PGC-1α is crucial because of its anti-inflammatory function, involving the modulation of microglial phenotypes and the integration of cellular energy metabolism. By elucidating the mechanisms and signaling pathways of PGC-1α in microglia, this research aims to identify novel therapeutic targets for addressing neuroinflammation in microglial cells associated with PD.

Gene mutations related to microglia in Parkinson’s disease

The majority of PD cases are idiopathic and are often linked to factors like aging, exposure to environmental poisons, and heavy metal accumulation. The advent of whole-genome CRISPR screening and bioinformatics analysis, coupled with a deeper understanding of PD, has triggered the recognition of over 100 genes or genetic loci associated with the disease (Ye et al., 2023). The mutations in autosomal dominant genes encompass those in the α-Syn (SNCA), leucine-rich repeat kinase 2 (LRRK2), vacuolar protein sorting 35 (VPS35), and low-density lipoprotein receptor-related protein 10 (LRP10). Conversely, mutations in autosomal recessive genes include Parkinsonism associated with neurodegeneration (PRKN), PTEN-induced kinase 1 (PINK1), and Parkinsonism-associated protein 7 (PARK7), which encode parkin, PINK1, and DJ-1, respectively, all exhibiting phenotypes analogous to those of idiopathic PD (Cherian et al., 2023). Specific PD-related genes exhibit a distinct association with the immune response of CNS microglia, with genes such as SNCA, LRRK2, PINK1, PRKN, and PARK7 implicated in these relationships (Marogianni et al., 2020).

Under physiological conditions, α-Syn can associate with lipid membranes to perform its physiological functions or form a tetrameric structure characterized by an α-helical conformation, effectively counteracting abnormal aggregation (Du et al., 2020). The SNCA gene primarily encodes α-Syn, and its five missense mutations—A30P, E46K, H50Q, G51D, and A53T—are involved in autosomal dominant PD (Tansey et al., 2022). Notably, the A30P and A53T mutant forms of α-Syn have a greater tendency to elicit immune responses in microglia, leading to increased secretion of pro-inflammatory cytokines and altered cellular phagocytic function. Pathological α-Syn activates microglia, which then engulf α-Syn into autophagosomes for degradation. p62, encoded by sequestosome 1 (SQSTM1), acts as a bridge between ubiquitinated proteins and autophagosomes within cells. Ubiquitinated mutant α-Syn binds to p62, which is subsequently transported to autophagosomes and degraded following lysosomal fusion. Pathological α-Syn interacts with TLR4 on the microglial surface, enhancing p62/SQSTM1 transcription via the NF-κB signaling pathway. This process is crucial for the autophagic degradation of α-Syn (Choi et al., 2020). Microglia carrying the A53T mutation exhibit an increased tendency for pro-inflammatory activation under inflammatory stimuli (Krzisch et al., 2024).

Encoded by the LRRK2 gene, LRRK2 is one of the most common genetic causes of familial PD (Sosero and Gan-Or, 2023). The LRRK2 protein plays a key role in regulating lysosomal activity, and mutations in the gene can impede α-Syn breakdown, leading to dysfunctional neurodegenerative processes in PD (Volta, 2023). LRRK2 inhibits lysosomal degradation in microglia by suppressing the levels and nuclear presence of the MIT-TFE transcription factor family containing transcription factor E3, transcription factor EB, transcription factor EC, and microphthalmia-associated transcription factor, all of which are vital for autophagy–lysosome biogenesis. In mouse brain microglia, inhibition and knockout of LRRK2 result in increased lysosomal proteolytic activity, whereas reduced activity is observed in cells exhibiting the LRRK2G2019S mutation, emphasizing the crucial role of LRRK2 in regulating lysosomal function in microglia (La Spina et al., 2020; Yadavalli and Ferguson, 2023). A highly effective and selective LRRK2 kinase inhibitor can correct the defects in mitochondrial autophagy linked to the LRRK2G2019S mutation and enhance mitochondrial autophagy in the microglia of wild-type mice (Singh et al., 2021). These findings demonstrate the essential function of LRRK2 in microglial cells, particularly with respect to the maintenance of intracellular functionality and homeostasis.

The regulation of mitochondrial autophagy is primarily governed by the parkin and PINK1 proteins, encoded by the PRKN and PINK1 genes, respectively. DJ-1, a small protein enzyme encoded by the PARK7 gene, is also a downstream player in this regulation, the impairment of which is genetically linked to a limited group of early-onset PD cases (Yan et al., 2014). Mitochondrial-encoded genes are highly enriched in the transcripts interacting with DJ-1, contributing to its protective role against oxidative stress damage. Besides its involvement in mitochondrial autophagy, DJ-1 regulates transcription and RNA binding, protecting neurons against cell death and oxidative stress (Lind-Holm Mogensen et al., 2023). DJ-1 prevents microglial activation and safeguards dopaminergic neurons by interacting with the p65 subunit of NF-κB in microglia. Increased TNF-α, IL-1β, and IL-6 were observed in BV2 cells lacking DJ-1, indicating increased neurotoxic effects in microglial cells (Lin et al., 2021). In DJ-1 low-expressing BV2 microglia, neuroinflammation and cell apoptosis mediated by microglia are accelerated through the Nrf2/thioredoxin 1/NLRP3 axis (Ji et al., 2020). The role of DJ-1 dysfunction in neuroinflammation has thus been highlighted, although the precise mechanisms have not been completely expounded.

Microglia-associated gene mutations in PD can lead to the upregulation or downregulation of related protein expression, resulting in pathological changes. This deepens our understanding of the mechanisms by which microglia contribute to neuroinflammation. Valuable therapeutic targets for treating neuroinflammation in PD can be identified by regulating specific genes to improve or restore microglial function.

Alzheimer’s disease

AD, a chronic neurodegenerative illness, is the most widespread form of dementia (Qiu et al., 2023). Its pathological characteristics encompass the accumulation of Aβ plaques, hyperphosphorylation of tau protein resulting in neurofibrillary tangles, and wide brain atrophy and neuronal loss (Hansen et al., 2018). Although the precise etiology of AD remains unclear, research suggests that the brain’s microglial and immune cells play important roles in the occurrence and development of the disease.

The function of microglial cells is considerably altered in the brains of patients with AD. The aberrant deposition of Aβ plaques and tau protein can directly activate microglial cells, triggering an immune response (Hansen et al., 2018). Microglial cells in patients with AD are frequently in the overactivation state. In addition to phagocytosing and clearing Aβ, microglia may also influence the surrounding neural environment by secreting neuroinflammatory factors. These microglia recognize Aβ through receptors like TLR4, which initiates an immune response and triggers the release of vast amounts of inflammatory mediators, including IL-1β, TNF-α, and NO (Sun et al., 2024). While these inflammatory factors may facilitate the short-term clearance of Aβ, prolonged excessive inflammation can cause neuronal injury and potentially exacerbate Aβ accumulation.

During the early phases of AD, microglial cells are typically capable of clearing Aβ from the brain effectively. However, as the disease progresses, the phagocytic function of microglial cells gradually diminishes, hindering their ability to remove Aβ deposits efficiently. This leads to the continuous accumulation of Aβ plaques, which triggers persistent immune responses that further exacerbate neurodegenerative damage (Baligács et al., 2024). The metabolic state of microglial cells influences their phagocytic capability to clear Aβ, alterations in surface receptors, imbalances in energy metabolism, and activating signals within the surrounding environment (Ennerfelt et al., 2022). As the condition worsens, microglial cells may migrate to damaged areas, exacerbating the local immune response and increasing neuronal death (Leng and Edison, 2021).

Microglial cell dysfunction is regarded as a critical factor in the advancement of AD. Neuroinflammation itself constitutes a crucial component of AD pathology. Microglial cells play a complex role in AD development, possessing a triple function in neuroinflammation, Aβ clearance, and neuroprotection, positioning them as a potential therapeutic target.

Regulating the immunity of microglial cells, mainly by inhibiting excessive inflammation, can slow the progression of AD. Altering the metabolic state of microglial cells or activating specific phagocytic pathways may enhance their ability to clear Aβ and other pathological substances, potentially delaying or reducing pathological accumulation in AD. Additionally, boosting microglial cells’ neuroprotective effects, such as increasing the secretion of neurotrophic factors, may improve neuronal survival and function. Given their important and complex role in the pathological processes of AD, microglial cells represent an emerging target for future AD therapies. Modulating their function may yield new possibilities for the treatment of this disease.

Multiple system atrophy

Multiple system atrophy (MSA) is a rare, chronic, neurodegenerative disease that mainly impacts the brain, cerebellum, basal ganglia, and autonomic nervous system. Typical symptoms include motor dysfunction, balance issues, blood pressure fluctuations, and urinary difficulties. Clinically, MSA often resembles PD; however, it progresses more rapidly and exhibits a poorer response to medication (Andersen et al., 2023).

As well as progressing more rapidly than PD, the core symptoms and pathological features of MSA also differ. A key pathological characteristic of MSA is the deposition of α-Syn in oligodendrocytes, which causes the formation of glial cytoplasmic inclusions. The aggregation of α-Syn into inclusion-like bodies directly impacts neuronal function and may also trigger neuroinflammation by activating microglial cells (Vieira et al., 2015). In MSA, there is a notable presence of activated microglial cells in the basal ganglia and cerebellar regions, particularly in areas involved in motor control (Vigen et al., 2021). These activated microglial cells promote local inflammatory responses by releasing cytokines (such as TNF-α and IL-1β) and chemical mediators (e.g., chemokines). Such inflammatory responses may exacerbate neurodegenerative changes, leading to increased neuronal damage.

The aggregation of α-Syn in the brains of patients with MSA can stimulate microglial cells through various mechanisms. First, α-Syn accumulation may directly bind to surface receptors on microglial cells, inducing their activation. Second, α-Syn aggregation may alter the signaling pathways between neurons and microglial cells, further promoting neuroinflammatory responses (Chavarría et al., 2022). In summary, the accumulation of α-Syn is not only a pathological hallmark of MSA but may also exacerbate disease progression by impairing microglial cell function. Activated microglial cells influence the neuronal environment by secreting cytokines and may also directly contribute to neuronal death by secreting cytotoxic molecules such as NO and ROS. In MSA, as neurodegenerative changes progress, activated microglial cells gradually become “accelerators” of cell death, thereby driving the rapid progression of the disease.

The BBB restricts the entry of external materials into the brain, sustaining the homeostasis of the neural environment. In patients with MSA, excessive activation of microglial cells may result in BBB leakage, permitting harmful external substances—such as immune cells, bacteria, or viruses—to infiltrate the CNS. This infiltration may further exacerbate inflammation and neuronal damage (Shibata et al., 2024). Consequently, it is suggested that microglial cells in MSA may play a role in worsening neuroinflammatory responses by compromising the integrity of the BBB.

As MSA progresses, activated microglial cells may lose their protective function and instead contribute to inflammation and the pathological progression of the disease. This dysregulation of microglial cells may represent a major factor in the worsening of symptoms experienced by patients with MSA. The function of microglial cells in MSA is intricate and multifaceted. They are involved in the neuroinflammatory response and may also become a key player in the etiological processes of neurodegeneration. By deepening our comprehension of the roles and mechanisms of microglial cells in MSA, we may uncover new insights into early disease diagnosis and therapy. Currently, research focusing on microglial cells as a therapeutic target is still in its infancy; however, future studies will likely open new avenues for MSA treatment with the ultimate aim of impeding the development of the disease.

Lewy body dementia

Lewy body dementia (LBD) is a prevalent neurodegenerative disease that features a gradual reduction in cognition function, motor impairments, and psychiatric symptoms, including hallucinations and behavioral changes. The pathological hallmark of LBD is the formation of Lewy bodies, which are abnormal α-Syn protein deposits typically found in CNS neurons (Loveland et al., 2023). Microglial cells can recognize these abnormal α-Syn aggregates and become activated through surface receptors such as TLRs and CD36 (Li and Wu, 2021; Gao et al., 2023). This activation is part of an immune reaction to clear abnormal proteins. However, in LBD, the over-aggregation of α-Syn surpasses the clearance capacity of microglial cells, leading to prolonged activation. This chronic activation fails to remove Lewy bodies effectively and triggers a cascade of inflammatory responses, which may result in further neuronal damage (Pereira-Iglesias et al., 2025). In the brains of patients with LBD, the overactivation of microglial cells tightly correlates with neuronal loss, most notably in areas associated with motor control and cognition, such as the basal ganglia and cerebral cortex. This inflammatory response correlates with the clinical symptoms of LBD, including motor impairments, cognitive decline, and the exacerbation of psychiatric symptoms (Taylor et al., 2020). Prolonged inflammation may disrupt the BBB, allowing harmful substances to invade and further exacerbate neuronal damage (Shibata et al., 2024). Additionally, the inflammatory response may alter synaptic transmission between neurons, contributing to the decline in cognitive and motor functions. The neuroinflammation triggered by microglial activation is also associated with psychiatric symptoms in patients with LBD, with hallucinations, depression, and behavioral changes potentially linked to the spread of inflammation in the brain.

Multiple sclerosis

MS is a chronic autoimmune disease of the CNS, primarily characterized by a progressive loss of neurological function. The pathological characteristics of MS include demyelination, neuroinflammation, and neuronal injury, particularly affecting white matter in the brain and spinal cord (Pukoli and Vécsei, 2023). The immune system targets the myelin sheath, leading to disrupted or abnormal nerve signal transmission. As myelin is damaged, the underlying nerve fibers may also be compromised, potentially resulting in permanent neurological impairment. During the acute phase of MS, the immune system becomes activated, triggering an autoimmune response that attacks the myelin sheath, leading to its destruction. Microglial cells play a crucial role in clearing myelin debris from the affected areas, a process known as “demyelination.” However, in patients with MS, excessive clearance of myelin debris by microglia can contribute to persistent neuronal injury and exacerbate the immune response. Concurrently, they may also hinder the nervous system’s repair processes, thereby slowing the rate of remyelination (Baaklini et al., 2023). Microglial cells detect damage and are activated through surface receptors, including TLRs and P2X receptors, which identify pathological signals. Upon activation, these cells release various inflammatory factors, like TNF-α, IL-1β, IL-6, IL-12, and CCL2, along with free radicals, resulting in additional neuronal damage. Furthermore, microglial cells are key players in the repair process following myelin damage in MS.

Although microglial cells play an active role in clearing damaged neurons and myelin debris, persistent overactivation in some cases may lead to a reduction in the regenerative capacity of myelin (McNamara et al., 2023). This overactivation is closely associated with a chronic inflammatory state, obstructing myelin repair and even exacerbating disease progression. During the chronic phase of MS, activated microglial cells may transform into a persistently activated state, continuously producing inflammatory factors (Yong and Yong, 2022). This chronic neuroinflammation is not only related to demyelinating damage but is also closely associated with neuronal injury and death.

The interaction between microglial cells and peripheral immunity is crucial for the pathogenesis of MS. Surrounding immune cells, particularly T and B cells, mount immune attacks against myelin and neurons in patients with MS. Microglial cells facilitate the transfer of these immune cells to lesion sites by secreting chemokines such as CCL2 (Shi et al., 2022). This influx of immune cells can exacerbate the inflammatory response, further damaging myelin and neurons. Concurrently, microglial cells can activate T cells through their antigen-presenting function, thereby establishing a vicious cycle (Shi et al., 2022).

Amyotrophic lateral sclerosis and frontotemporal dementia

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that mainly impacts motor neurons and triggers muscle paralysis, weakness, and atrophy (Lall and Baloh, 2017). In patients with ALS, motor neurons in the spinal cord and cortex gradually degenerate, ultimately resulting in cell death. Additionally, microglial cells near these motor neurons are often over-activated. The inflammatory factors released by these microglial cells, including cytokines, ROS, and other harmful molecules, might exacerbate neuronal degeneration. This inflammatory response is considerably associated with motor neuron death. The excessive activation of microglial cells and sustained neuroinflammation may contribute to the swift development of ALS and the early mortality of patients. With respect to genetic factors and the role of microglial cells in certain genetic forms of ALS, such as those involving the superoxide dismutase 1 mutation, the level of microglial activation may be related to the rate of disease progression. The superoxide dismutase 1 mutation not only impacts the function of motor neurons but may also alter microglial cell function, further aggravating the disease process (Mead et al., 2023).

Frontotemporal dementia (FTD) is a category of dementia characterized by the degeneration of neurons in the frontal and temporal lobes. Early FTD symptoms typically include changes in personality, behavioral abnormalities, and language impairments. In FTD, the activation of microglial cells may exacerbate neurodegeneration—overactive microglial cells secrete inflammatory factors like IL-1β and TNF-α, which can further worsen neuronal damage. Neuroinflammatory reactions might be a vital player in the development of FTD, particularly during its early phases. Similar to ALS, certain genetic cases of FTD also relate to microglial cell dysfunction. For instance, mutations in genes such as TAR DNA-binding protein 43 (TARDBP), chromosome 9 open reading frame 72 (C9orf72), or microtubule-associated protein tau may not only directly impact neuronal function but also modify the function of microglial cells, resulting in abnormal neuroinflammatory responses that facilitate the onset and progression of FTD (De Marchi et al., 2023).

There is a notable overlap between FTD and ALS, and approximately 10%–15% of patients with ALS develop symptoms indicative of FTD. These cases are commonly referred to as “ALS-FTD spectrum disorders” (Lall and Baloh, 2017). This phenomenon suggests that the two conditions may share underlying pathological mechanisms. In patients with ALS-FTD spectrum disorders, activating neuroinflammatory reactions and microglial cells may represent common pathological features of both diseases. These neurodegenerative changes are potentially associated with the abnormal aggregation of specific proteins. Notably, the abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) is a critical pathological characteristic observed in ALS and FTD. TDP-43 exhibits abnormal deposition in both conditions, particularly within motor neurons and neurons located in the frontal and temporal lobes (Zhuo et al., 2020). Although the function of tau protein in ALS is relatively limited, some patients exhibit accumulation of tau protein. The C9orf72 gene mutation is a widespread genetic factor found in ALS and FTD, particularly in familial cases. The repeat expansion linked to this mutation may trigger TDP-43 aggregation and promote neurodegenerative changes (De Marchi et al., 2023). The motor neurons in the spinal cord and cerebral cortex are primarily affected in ALS, while in FTD, the neurons in the frontal and temporal lobes are predominantly impacted. Patients with ALS and FTD demonstrate abnormal inflammatory reactions in their brains, which accelerate neuronal degradation and death; the overactivation of microglial cells worsens both conditions.

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that falls within the spectrum of Parkinsonism. It is primarily characterized by movement disorders, gait instability, eye movement abnormalities, and language and cognitive function decline (Couto et al., 2022). The pathological features of PSP include neuronal damage in the basal ganglia, brainstem, and frontal-temporal cortical regions, particularly affecting the neural structures responsible for controlling eye movements and maintaining postural balance. In the brains of patients with PSP, there is an abnormal aggregation of tau protein, which forms neurofibrillary tangles (Couto et al., 2022). These tangles are primarily distributed in the brainstem, basal ganglia, frontal lobes, and other associated areas, leading to neuronal death and functional loss. Microglial cells can recognize the abnormal aggregation of tau protein through their surface receptors and initiate an immune response. This immune response may become self-perpetuating; upon detecting the abnormal tau aggregation, microglial cells release inflammatory factors that further drive the progression of tau pathology. The density and activation levels of microglial cells are significantly increased in the brain tissue of patients with PSP, particularly in the regions most severely affected, like the basal ganglia, brainstem, and frontal-temporal cortical areas (Hemonnot et al., 2019). By secreting inflammatory factors, microglial cells may exacerbate local neuroinflammation, promoting the abnormal aggregation of tau protein and subsequent neuronal death. This abnormal aggregation of tau may directly stimulate the activation of microglial cells, creating a vicious cycle that further intensifies the neuroinflammatory response and contributes to increased neuronal damage (Hemonnot et al., 2019). When microglial cell functions are suppressed, tau protein aggregation and the associated neuronal damage are significantly reduced (Gratuze et al., 2021). This finding offers insights into potential strategies for alleviating PSP and other similar neurodegenerative diseases.

Corticobasal degeneration

Corticobasal degeneration (CBD) is a neurodegenerative disorder primarily characterized by asymmetric motor disorders, with symptoms that include movement abnormalities, cognitive impairments, and behavioral changes. Pathological features of CBD encompass degenerative variations in the neurons of the basal ganglia and cortical regions, particularly the abnormal accumulation of tau protein around neurons and synapses (Liu et al., 2023a). The misfolding and accumulation of tau protein create tau inclusions, and microglial cells are involved in the clearance of these tau deposits (Španić et al., 2019). However, in CBD, the accumulation of tau protein may surpass the clearing capacity of microglial cells. Neuronal damage within the basal ganglia and cortical regions in CBD triggers the activation of microglial cells. Once activated, these cells secrete many inflammatory factors, further exacerbating local neuroinflammatory responses. The accumulation of inflammatory factors, including TNF-α, IL-1β, and IL-6, in these regions is closely associated with the neurodegenerative process. Overinflammation might worsen neuronal injury and degeneration, triggering a profound reduction in motor and cognitive functions. Microglial cells recognize tau protein through their receptors, including TLRs, and attempt to mitigate its accumulation in the brain by phagocytosing and clearing it (Li and Wu, 2021). However, the aberrant accumulation of tau protein may cause excessive activation of microglial cells, triggering a stronger inflammatory response. This process could create a vicious cycle, further exacerbating neurodegeneration (Chen and Yu, 2023). Microglial cells, phagocytosing dead or damaged neurons and clearing abnormal proteins, might serve as a protective factor in sustaining the homeostasis of the neural environment (Kwon and Koh, 2020). In CBD, this protective function of microglial cells is often overshadowed by their prolonged activation. The repair function of microglial cells may be suppressed because of the long-term chronic inflammatory response, and they may instead shift to harmful immune responses, leading to sustained damage to the nervous system.

Huntington’s disease

Huntingdon’s disease (HD) is a genetic neurodegenerative disorder arising from a mutation in the Huntington gene (HTT), which causes an abnormally long repeat of glutamine sequences, resulting in the production of pathological Huntington protein (mHTT) (Medina et al., 2022). HD typically manifests between the ages of 30 and 50 years, with clinical features including chorea (involuntary movements), cognitive impairments, and emotional instability. As the disease progresses, patients experience considerable motor, mental, and psychiatric disturbances, ultimately leading to death (McColgan and Tabrizi, 2018). The accumulation of abnormal mHTT, neuronal damage, oxidative stress, and inflammatory responses are critical pathogenic mechanisms in HD. Microglial cells exhibit a sustained activation state in the brain tissue of patients with HD. The toxic effects of mHTT may trigger this activation. mHTT interacts with receptors on the microglial cell surface, triggering their activation and the secretion of inflammatory factors (such as TNF-α, and IL-1β), which promote neuronal damage and disease progression (Wilton et al., 2023). This activation leads to local neuroinflammation and may exacerbate the pathological process by disrupting the interactions between neurons and glial cells. In HD, microglial cells exhibit sustained activation and may increase their migratory capacity toward the affected areas. Through their phagocytic activity, microglial cells precisely target damaged neurons or synapses (O’Regan et al., 2021). Although this response is a normal reaction of the CNS to injury, if not adequately regulated, it may exacerbate neurodegenerative changes.

Strategies for Targeted Treatment of Microglia

In view of the key role of microglia in neurodegenerative disorders, researchers are investigating a range of therapeutic strategies to target these cells. These strategies primarily include immune modulation, inhibition of excessive activation, promotion of clearance functions, and reversal of microglial dysfunction. The excessive activation of microglia is often accompanied by the release of pro-inflammatory factors, making the inhibition of microglial overactivation an essential therapeutic strategy.

Various microglial inhibitors have been proposed, among which the colony-stimulating factor 1 receptor (CSF1R) serves as a crucial receptor for microglial proliferation and survival. CSF1R is intimately associated with the development, function, and activation of microglia. Consequently, inhibiting CSF1R activity can effectively mitigate microglial overactivation, thereby alleviating inflammation in the brain (Xiang et al., 2023). PLX3397, a small-molecule CSF1R inhibitor, has demonstrated efficacy in improving neurodegenerative disorders in animal models of AD. PLX3397 effectively suppresses microglial activation, decreases the secretion of pro-inflammatory factors, and enhances cognitive function (Sosna et al., 2018). The application of CSF1R inhibitors highlights their potential to slow disease progression in neurodegenerative disorders by modulating immune responses.

Microglia in the nervous system serve functions that extend beyond inflammation, including supporting neural repair and clearing harmful substances. Consequently, regulating the activation state of microglia to maintain a balance between neuroprotection and inflammation is a crucial therapeutic target. By locally modulating microglial function, it is possible to alleviate disease symptoms without completely inhibiting their immune functions.

Several clinical drugs have been shown to regulate the activation state of microglia through various mechanisms, influencing therapeutic outcomes in neurodegenerative diseases. Nonsteroidal anti-inflammatory drugs, such as aspirin and indomethacin, inhibit cyclooxygenase activity, reducing the production of inflammatory factors. Studies suggest that nonsteroidal anti-inflammatory drugs can suppress microglial activation and reduce brain inflammation in patients with AD, potentially slowing disease progression (Kaduševičius, 2021). Nonetheless, the long-standing influence of nonsteroidal anti-inflammatory drugs on neuroprotection is still controversial. Some antidepressants, particularly selective serotonin reuptake inhibitors, have been found to alleviate neuroinflammation by modulating microglial function. Selective serotonin reuptake inhibitors can reduce microglia’s release of inflammatory mediators, thus improving the immune microenvironment of the nervous system and becoming an auxiliary player in the therapy of neurodegenerative disorders (Sun et al., 2022). Immunomodulators, like abacavir and rituximab, can mitigate the overactivation of microglia by modulating the activity of the immune system, thereby slowing the progression of neuroinflammation (Fornari Laurindo et al., 2023). Neurotrophic factors, including brain-derived neurotrophic factor and nerve growth factor, play a crucial role in regulating the function of microglial cells by inhibiting inflammatory responses and promoting neuroprotection. Specific pharmacological agents, such as enalapril and sildenafil, can enhance the expression of neurotrophic factors, diminish M1 activation of microglial cells, and facilitate M2 polarization, ultimately alleviating the symptoms associated with neurodegenerative diseases (Nunes et al., 2015).

Neurodegenerative diseases are frequently linked to heightened oxidative stress. Antioxidants can mitigate the activation of microglial cells by eliminating excessive free radicals, thereby reducing their abnormal activation (Woodburn et al., 2021). For instance, specific antioxidants such as vitamin E and resveratrol have been investigated for their potential to diminish the M1 activation of microglial cells, suppress neuroinflammation, and hinder the progression of neurodegenerative diseases (Kenchappa et al., 2022).

Natural products have drawn increasing attention in the therapy of neurodegenerative diseases, with numerous natural compounds demonstrating the potential to regulate microglial function. Flavonoids such as quercetin are plant-derived antioxidants with anti-inflammatory and neuroprotective effects. Such compounds have been proven to mitigate symptoms of AD and PD by inhibiting excessive microglial activation and reducing neuroinflammation (Zhang and Yan, 2023). Ginsenosides, a key component of traditional Chinese medicine, also exhibit the potential to regulate microglial activation. Vinoth Kumar et al. (2016) suggest that ginsenosides can effectively inhibit microglial activation and the producion of pro-inflammatory cytokines by regulating the TGF-β1/Smad pathway, thereby promoting neurorepair. Similarly, alkaloids, such as cytisine primarily reduce neuroinflammation by inhibiting microglial inflammatory responses, alleviating neuronal damage and improving symptoms associated with neurodegenerative diseases like PD (Bhusal et al., 2023). Using a tau protein mouse model, Sun et al. (2021) proved that rutin, a natural flavonoid glycoside, could impede the progress of glial cells and mitigate neuroinflammatory responses by downregulating the NF-κB pathway. This reduction in pro-inflammatory factors curtailed excessive phagocytosis of synapses by microglial cells, effectively slowing synapse loss.

Microglia possess neuroprotective functions and the capacity to trigger neuroinflammation. Consequently, therapeutic strategies targeting microglia—such as inhibiting excessive activation, regulating immune responses, and promoting neurorepair—have emerged as major research areas. While clinical drugs and natural products can modulate microglial activity to some extent, the therapeutic effects remain limited, and considerable variability exists in individual responses. Future research must further investigate the mechanisms underlying microglial function and explore how to more precisely regulate the activity of these cells to provide more effective and personalized treatment options for neurodegenerative diseases.

Conclusion and Future Perspectives

There is an increasing concern about the neuroimmune inflammatory functions of microglia regarding the progress of neurodegenerative diseases. Timely intervention in neuroinflammation could potentially improve the prognosis for individuals with neurodegenerative diseases. Our review summarizes the present advancements in understanding the regulatory factors that influence microglia in PD, their involvement in novel cell death mechanisms, neuroinflammatory responses mediated by membrane receptors, and the process of lysosomal acidification within microglia. In conclusion, microglia function as pivotal immune regulatory cells within the nervous system and become a multifaceted and critical player in the progression of neurodegenerative diseases. Advancing our understanding of their functions and the mechanisms that govern them is expected to yield new insights and potential therapeutic targets for elucidating the pathophysiology of neurodegenerative diseases and fostering the development of innovative treatment strategies. We hope to translate these research findings into applications in preclinical and clinical stages, thereby addressing the current limitations of the neurodegenerative disease treatment options. By thoroughly exploring these regulatory factors and potential targets, we aim to provide novel insights and approaches for the clinical treatment of neurodegenerative diseases, advance neurodegenerative disease research, and ultimately enhance the quality of life for those affected by the condition. Although the role of microglial cells in neurodegenerative diseases has been extensively studied, the specific mechanisms by which they contribute to the disease across different pathological stages and among various individuals remain inadequately understood. Microglial cells are implicated in inflammation; however, they may also influence neurodegenerative processes through various signaling pathways, receptors, and factors, rendering their role highly complex and resistant to simplification into a single model. Presently, many neurodegenerative disease studies utilize animal or cell models, which may not fully capture the complexity and heterogeneity characteristic of human neurodegenerative diseases, thus limiting the translational potential and clinical applicability of the findings. Despite significant advancements in understanding microglial cells through basic research, translating these discoveries into preclinical and clinical applications encounters several challenges. Strategies to modulate microglial function, inflammatory responses, or lysosomal acidification may face obstacles related to drug delivery, treatment timing, and potential side effects in practical applications.

Furthermore, genetic differences among individuals may result in varying microglial responses. Even under similar pathological conditions, treatment strategies may yield different effects based on an individual’s genetic background, complicating treatment approaches. While microglial cells are considered promising therapeutic targets, selectively modulating their function without eliciting undesirable side effects remains a significant challenge. Effectively intervening in microglial activity without disrupting their normal immune functions continues to be an unresolved issue. The current evaluation and clinical trial design standards lack uniformity, complicating the comparison and integration of findings across different studies. Although research on microglial cells in neurodegenerative diseases has advanced rapidly, these studies face numerous challenges.

Funding Statement

Funding:
This work was funded by the Science and Technology Research of Henan Province, No. 242103810041 (to JY).

Footnotes

Conflicts of interest:
The authors declare that they have no competing interests.

C-Editor: Zhao M; S-Editors: Yu J, Li CH; L-Editors: Yu J, Song LP; T-Editor: Jia Y

Data availability statement:

Not applicable .

References

Associated Data

Data Availability Statement

Not applicable .