Microglial polarization in Alzheimer's disease: Mechanisms,implications,and therapeutic opportunities

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Microglial cells, the resident immune cells in the central nervous system, play a crucial role in the pathogenesis of AD. Microglia can undergo polarization, shifting between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in response to different stimuli. Dysregulation of microglial polarization towards the pro-inflammatory phenotype leads to the release of inflammatory cytokines, oxidative stress, and synaptic dysfunction. These processes contribute to neuronal damage and cognitive decline in AD. However, several challenges remain in this field. The complex molecular mechanisms governing microglial polarization in AD need to be further elucidated. In this review, we discuss the mechanisms underlying microglial polarization in AD and its implications in disease progression.

Keywords

Alzheimer's disease implications microglial polarization neuroinflammation mechanisms

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is the most common form of dementia, affecting millions of individuals worldwide.¹ The pathogenesis of AD is complex and involves various cellular and molecular mechanisms, including the activation and polarization of microglia, the resident immune cells of the central nervous system.² Microglia are key players in the innate immune response and play a crucial role in maintaining brain homeostasis.³ In response to injury or pathological stimuli, microglia become activated and undergo a phenotypic transformation known as polarization. Microglial polarization can be broadly categorized into two main states: the classical pro-inflammatory M1 phenotype and the alternative anti-inflammatory M2 phenotype.⁴ These polarization states have distinct functional properties and are associated with different disease outcomes. In the context of AD, the role of microglial polarization is a topic of intense research. Accumulating evidence suggests that microglia in AD brains exhibit a predominantly pro-inflammatory M1 phenotype, characterized by the release of pro-inflammatory cytokines, reactive oxygen species, and neurotoxic factors. This chronic neuroinflammation mediated by M1 microglia contributes to the progression of AD pathology, including the accumulation of amyloid-β plaques and the formation of neurofibrillary tangles.⁵ On the other hand, the M2 phenotype of microglia is associated with tissue repair, phagocytosis of debris, and the release of anti-inflammatory cytokines.⁶ However, in AD, the M2 phenotype is often impaired, leading to an imbalance between pro-inflammatory and anti-inflammatory microglial responses. This dysregulated microglial polarization further exacerbates neuroinflammation and neuronal damage in AD.⁷ Understanding the mechanisms underlying microglial polarization in AD is of utmost importance for the development of effective therapeutic strategies. Several signaling pathways and molecular regulators have been implicated in microglial polarization, including the nuclear factor-kappaB (NF-κB), toll-like receptors (TLRs).⁸ Targeting these pathways and molecules may offer potential therapeutic opportunities for modulating microglial polarization and attenuating neuroinflammation in AD.

In this review, we will discuss the mechanisms and implications of microglial polarization in AD pathogenesis. We will explore the molecular pathways and regulators involved in microglial polarization and highlight the therapeutic potential of targeting microglia for AD treatment. By elucidating the intricate interplay between microglial polarization and AD pathology, we aim to provide insights into novel therapeutic approaches that can mitigate neuroinflammation and slow down disease progression in AD.

Microglial polarization and its functional states

Definition and classification of microglial polarization

Microglial polarization refers to the ability of microglia to adopt different phenotypic and functional states in response to various stimuli. The two main polarized states of microglia are the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. These phenotypes are characterized by different gene expression profiles and release distinct sets of cytokines and other immune mediators. Microglial polarization is influenced by various factors, including cues from the microenvironment and pathological stimuli. These factors can drive microglia towards different polarization states. Within the M1 phenotype, there are two subtypes: the classical M1 phenotype, which is induced by pro-inflammatory stimuli such as lipopolysaccharide (LPS) or interferon-gamma (IFN-γ), and the alternative M1 phenotype, which is induced by other inflammatory signals. Within the M2 phenotype, there are three subtypes: the M2a phenotype, induced by interleukin-4 (IL-4) or IL-13, the M2b phenotype, induced by immune complexes or TLR agonists, and the M2c phenotype, induced by IL-10 or glucocorticoids.^9,10 Different markers and characteristics are associated with each microglial polarization state. M1 polarization is typically characterized by the expression of markers such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). On the other hand, M2 polarization is characterized by the expression of markers such as arginase-1 (Arg1), transforming growth factor-beta (TGF-β), and interleukin-10 (IL-10).¹¹ The different microglial polarization states have distinct functional implications. M1 polarization is associated with pro-inflammatory responses and the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, contributing to neuroinflammation and tissue damage. In contrast, M2 polarization is associated with anti-inflammatory and tissue repair processes, promoting neuroprotection and tissue remodeling.¹² Imbalance between M1 and M2 polarization has been implicated in various neurodegenerative diseases, where excessive M1 polarization and insufficient M2 polarization can contribute to disease progression.¹³ Targeting microglial polarization holds potential therapeutic implications for neurodegenerative diseases, as modulating microglial phenotypes could help restore the balance between inflammation and tissue repair in the CNS¹⁴ (Figure 1).

Figure 1.

Different microglial cell phenotypes.

Pro-inflammatory M1 phenotype and its impaired function in AD

The pro-inflammatory M1 phenotype of microglia plays a significant role in the pathology of AD. In AD, microglia are activated and polarized towards the M1 phenotype in response to Aβ plaques.¹⁵ Aβ can activate microglia through various mechanisms, including binding to TLRs and triggering the release of pro-inflammatory cytokines.¹⁶ M1 microglia release pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. These cytokines contribute to neuroinflammation, which can exacerbate neuronal damage and promote the progression of AD pathology.^17,18 Additionally, M1 microglia release ROS as part of their immune response. Excessive ROS production can lead to oxidative stress, which damages neurons and exacerbates neurodegeneration in AD.¹⁹ One important aspect of M1 microglia in AD is their impaired phagocytic activity, leading to a decreased ability to clear Aβ plaques. This impaired clearance contributes to the accumulation of Aβ in the brain, which is a hallmark feature of AD.²⁰ Moreover, M1 microglia can release cytotoxic factors, including NO and excitotoxic glutamate, which can directly damage neurons. This neuronal toxicity further contributes to neurodegeneration in AD.²¹ Additionally, M1 microglia can disrupt synaptic function by releasing factors that impair synaptic plasticity and neurotransmitter release. This disruption of synaptic function contributes to cognitive impairments observed in AD.²² Overall, the pro-inflammatory M1 phenotype of microglia plays a detrimental role in AD pathology by promoting neuroinflammation, impairing Aβ clearance, inducing oxidative stress, causing neuronal toxicity, and disrupting synaptic function. Therefore, targeting M1 microglial activation and promoting a shift towards the anti-inflammatory M2 phenotype may hold therapeutic potential for mitigating neuroinflammation and slowing down the progression of AD.

Anti-inflammatory M2 phenotype and its impaired function in AD

The M2 phenotype of microglia, known for its neuroprotective and tissue repair functions, is impaired in AD.²³ In AD, there is a shift away from the M2 phenotype towards the pro-inflammatory M1 phenotype, driven by chronic neuroinflammation and the accumulation of Aβ plaques. This shift hinders the clearance of Aβ by M2 microglia, leading to its accumulation and the progression of AD pathology.²⁴ M2 microglia produce anti-inflammatory cytokines, such as IL-10 and TGF-β, which regulate the immune response and promote tissue repair.²⁵ However, in AD, the production of these cytokines is reduced, resulting in a dysregulated immune response and increased neuroinflammation.²⁶ M2 microglia also secrete trophic factors, like BDNF and IGF-1, which support neuronal survival and function. In AD, the impaired M2 phenotype leads to reduced secretion of these trophic factors, contributing to neuronal dysfunction and degeneration.²⁷ The impaired M2 phenotype in AD disrupts the balance between pro-inflammatory and anti-inflammatory factors, leading to chronic neuroinflammation and neuronal damage.²⁸ Additionally, the impaired M2 phenotype hinders the resolution of inflammation, further perpetuating the neuroinflammatory state in AD.²⁹ Overall, the impaired function of the M2 phenotype in AD results in impaired phagocytic clearance, reduced anti-inflammatory cytokine production, altered trophic factor secretion, and impaired resolution of inflammation. Restoring the function of the M2 phenotype or promoting its polarization may have therapeutic potential for reducing neuroinflammation and promoting tissue repair in AD.

Mechanisms of microglial polarization in AD

Signaling pathways involved in microglial polarization

Nuclear factor-kappaB (NF-κB) pathway

The NF-κB pathway is crucial for the polarization of microglia, which involves the regulation of M1 and M2 phenotypes.³⁰ Various stimuli, including TNF-α, IL-1β, and LPS, activate the NF-κB pathway.³¹ When activated, NF-κB moves to the nucleus and controls the expression of genes related to immune responses.³² Activation of the NF-κB pathway in microglia promotes the M1 pro-inflammatory phenotype. This leads to the production of pro-inflammatory cytokines, chemokines, and iNOS, resulting in the release of inflammatory mediators and ROS.³³ M1 polarization contributes to neuroinflammation and tissue damage. However, the NF-κB pathway can also regulate the polarization of microglia toward the M2 anti-inflammatory phenotype.³⁴ Factors like IL-4, IL-13, IL-10, and glucocorticoids can activate the NF-κB pathway and promote M2 polarization_.^35–38 NF-κB induces the expression of anti-inflammatory cytokines scavenger receptors, and neurotrophic factors, which aid in tissue repair and immunoregulation.^39–41 The NF-κB pathway interacts with other signaling pathways involved in microglial polarization. For example, the cAMP response element-binding protein (CREB) pathway, which promotes M2 polarization, can modulate the activation of the NF-κB pathway.⁴² TLRs can also activate NF-κB, leading to M1 polarization. In neurodegenerative diseases like AD and Parkinson's disease (PD), the NF-κB pathway can become dysregulated, resulting in sustained activation and a biased microglial polarization towards the M1 phenotype. This sustained activation contributes to chronic neuroinflammation and neuronal damage.^43,44 Targeting the NF-κB pathway holds potential for modulating microglial polarization and reducing neuroinflammation in these conditions.

Toll-like receptors (TLRs) signaling

TLRs are a type of pattern recognition receptors (PRRs) found on the surface of microglia and other immune cells. They play a crucial role in recognizing patterns associated with pathogens (PAMPs) and tissue damage (DAMPs). TLR signaling influences the activation and phenotypic shift of microglia by initiating signaling cascades upon ligand binding.⁴⁵ Different TLRs recognize specific ligands, such as TLR4 recognizing LPS and TLR2 recognizing bacterial lipoproteins.⁴⁶ Activation of TLRs leads to the activation of downstream signaling pathways like the NF-κB and MAPK pathways, resulting in the release of pro-inflammatory cytokines and chemokines, promoting the M1 pro-inflammatory phenotype.⁴⁷ However, TLR signaling can also induce the expression of anti-inflammatory cytokines, scavenger receptors, and neurotrophic factors associated with the M2 anti-inflammatory phenotype Targeting TLR signaling pathways may hold potential for regulating microglial polarization and reducing neuroinflammation in these conditions.^48–50

Molecular regulators of microglial polarization

CX3CR1

CX3CL1 (Fractalkine) is a transmembrane chemokine expressed by neurons in the central nervous system (CNS), which primarily interacts with its sole receptor, CX3CR1, expressed mainly on microglia.⁵¹ CX3CR1 signaling plays a crucial role in the homeostasis, proliferation, migration, and phagocytosis of microglia. In a healthy state, CX3CR1 inhibits excessive activation and inflammatory responses of microglia, thereby protecting neurons. We have also discovered that CX3CR1 deficiency exerts different effects on Aβ and tau pathologies in AD, facilitating Aβ deposition but potentially exacerbating tau pathology. This suggests that CX3CR1 deficiency intensifies the pathological progression of AD. Furthermore, CX3CR1 deficiency leads to the polarization of microglia towards the M1 phenotype, upregulation of proinflammatory factors, and downregulation of anti-inflammatory factors.⁵² Therefore, enhancing CX3CR1 upregulation can promote neural recovery, improve cognition, and delay the progression of AD.

Triggering receptor expressed on myeloid cells 2 (TREM2)

TREM2 is a cell surface receptor that is predominantly expressed by microglia in the central nervous system. It plays a critical role in regulating microglial polarization and function.⁵³ TREM2 is involved in various cellular processes, including phagocytosis, cytokine production, and inflammatory response TREM2 has been shown to promote the shift of microglia towards an anti-inflammatory M2 phenotype. Activation of TREM2 signaling leads to the upregulation of anti-inflammatory cytokines.⁵⁴ This promotes a neuroprotective and tissue repair response. Furthermore, TREM2 is involved in the clearance of apoptotic cells and debris through phagocytosis.⁵⁵ Mutations in the TREM2 gene have been associated with increased risk for several neurodegenerative diseases, including AD and PD. These mutations impair the function of TREM2 and lead to dysregulated microglial activation and polarization, resulting in chronic neuroinflammation and neurodegeneration. Targeting TREM2 signaling pathway has emerged as a potential therapeutic strategy for neurodegenerative diseases. Enhancing TREM2 activation or function could promote microglial polarization towards an anti-inflammatory phenotype and enhance phagocytic clearance, thereby reducing neuroinflammation and neurodegeneration.^56,57

Interleukin-4 (Il-4) and Il-13

IL-4 and IL-13 are anti-inflammatory cytokines that play a crucial role in microglial polarization and function. These cytokines induce the M2 anti-inflammatory phenotype in microglia. IL-4 and IL-13 can be produced by various immune cells, including T cells and mast cells, as well as by microglia themselves.^58,59 When IL-4 or IL-13 binds to their respective receptors on microglia, they activate signaling pathways that promote M2 polarization. IL-4 and IL-13 can interact with other signaling pathways involved in microglial polarization, including TREM2 signaling and IFN-γ signaling, which can modulate the balance between M1 and M2 polarization.^60,61 Overall, IL-4 and IL-13 are potent regulators of microglial polarization, promoting the shift towards an anti-inflammatory M2 phenotype. Exploiting the therapeutic potential of IL-4 and IL-13 or targeting their signaling pathways may offer strategies to modulate microglial activation and reduce neuroinflammation in various neurological disorders.

Peroxisome proliferator-activated receptor gamma (PPARγ)

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a vital role in regulating microglial polarization and function When PPARγ is activated by ligands like thiazolidinediones (TZDs), it promotes the polarization of microglia towards the anti-inflammatory M2 phenotype.⁶² This activation leads to the expression of genes associated with the M2 phenotype, which are involved in tissue repair and anti-inflammatory processes.⁶³ One of the key effects of PPARγ activation is the inhibition of pro-inflammatory cytokine production by microglia. It suppresses the production of cytokines like TNF-α, IL-1β, and IL-6 by interfering with the signaling pathways that lead to their production. By doing so, PPARγ helps reduce neuroinflammation and create a more anti-inflammatory environment.⁶⁴ Additionally, PPARγ activation enhances the phagocytic activity of microglia, allowing them to efficiently clear cellular debris and promote tissue repair.⁶⁵ It also regulates the expression of genes involved in phagocytosis, such as CD36 and SR-A, which are important for clearing apoptotic cells and debris.^66,67 PPARγ activation has further benefits in reducing oxidative stress and neurotoxicity in microglia.⁶⁸ It regulates the expression of antioxidant enzymes like SOD and catalase, which help counteract oxidative damage. PPARγ activation also inhibits the production of neurotoxic factors like NO and ROS by microglia.⁶⁹ Moreover, PPARγ can interact with other signaling pathways involved in microglial polarization. It can synergize with IL-4and IL-13 signaling to enhance the M2 phenotype.⁷⁰ Overall, PPARγ is a crucial regulator of microglial polarization, promoting the shift towards an anti-inflammatory M2 phenotype. Activating PPARγ has shown therapeutic potential in various neuroinflammatory and neurodegenerative disorders, suggesting that targeting PPARγ signaling may be a promising strategy to modulate microglial activation and reduce neuroinflammation (Figure 2).

Figure 2.

Mechanisms of microglial polarization: By interacting with related cytokines CX3CR1, TREM2, PPAR γ, IL-4, and IL-13 through the NF-κB pathway and TLRs pathway, the growth of pro-inflammatory factors is inhibited, anti-inflammatory factors are promoted, and microglia are polarized towards M2 type.

Therapeutic opportunities targeting microglial polarization in AD

Microglia play a pivotal role in the pathogenesis and treatment of AD, making modulation of their function a promising therapeutic target.

NSAIDs

NSAIDs are a class of drugs widely used worldwide, with analgesic, anti-inflammatory, and antipyretic effects. NSAIDs have become one of the largest prescription drugs, accounting for 5% of global prescription drugs.⁷¹ NSAIDs inhibit cyclooxygenase (COX), reducing inflammatory mediators and alleviating inflammation and pain. Epidemiological studies suggest that long-term NSAID use may reduce AD pathology. NSAIDs theoretically mitigate neuroinflammation in AD by inhibiting COX and reducing inflammatory mediator production, as well as inhibiting microglial M1 polarization and alleviating inflammatory responses. For example, diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) that has been approved by the FDA for the treatment of various inflammatory diseases. Early studies did not find significant benefits of traditional NSAIDs (such as indomethacin, celecoxib, etc.) for AD, but diclofenac sodium has shown potential to reduce the risk of AD in retrospective cohort studies. Diclofenac sodium can inhibit the activation of pro-inflammatory cytokines and alleviate neuroinflammation by activating NLRP3 inflammasomes.⁷² However, in clinical diagnosis, we find limited efficacy in confirmed AD patients, possibly due to the complex AD pathology or inability to effectively target microglial activation pathways. Thus, NSAIDs may serve as palliative therapy rather than disease-modifying agents.^73,74

Glucocorticoids

GCs are a group of steroid hormones produced by the adrenal cortex, induced by stress and circadian rhythms. Studies have found that in neurodegenerative diseases, abnormal levels of glucocorticoids promote neuronal damage, exacerbate neuroinflammation, and oxidative stress responses Corticosteroids have bidirectional effects and are widely used in clinical practice due to their strong anti-inflammatory and immune suppressive effects. In the central nervous system, long-term exposure to the glucocorticoid environment can activate microglial polarization, produce pro-inflammatory factors, and induce neuroinflammation.^75,76 For example, studies have found that long-term use of glucocorticoids leads to the release of HMGB1, a widely present non histone chromatin protein. As one of the risk-associated molecular patterns (DAMPs), HMGB1 has pro-inflammatory effects by binding toTLR4, RAGE and other receptors, inducing polarization of microglia and exacerbating neuroinflammatory reactions. However, the use of glucocorticoid receptor antagonists (such as mifepristone) significantly inhibits the release of HMGB1 induced by corticosterone, reducing neuroinflammation, reversing or delaying AD lesions_.⁷⁷

Antioxidants

Oxidative stress is caused by excessive production of free radicals and ROS, leading to organelle damage and functional impairment.⁷⁸ Oxidative stress plays an important role in the onset and progression of AD, and antioxidants can alleviate oxidative stress, protect neurons, and delay AD. Antioxidants mainly neutralize ROS through enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), inhibiting ROS induced release of pro-inflammatory cytokines in microglia and reducing nerve damage. Antioxidants are widely available and can be obtained from plants, food, supplements, and other sources. For example, vitamins, carotenoids, and other natural compounds.⁷⁹

Natural compounds

Natural compounds from plants, organisms, microorganisms, and marine sources have therapeutic effects, including neuroinflammation modulation. Multiple natural compounds inhibit neuroinflammation in AD, e.g., curcumin (anti-inflammatory, antioxidant, promotes M2 microglial polarization, reduces neurodamage).^80,81 and resveratrol (anti-inflammatory, antioxidant, inhibits M1 polarization, reduces inflammatory cytokines, resists oxidative stress-induced neurodamage, promotes M2 polarization).⁸² Despite therapeutic potential, anti-inflammatory mechanisms require further study, and clinical efficacy varies.

Neurotransmitter receptors

Neurotransmitter receptors are specific markers of neurons. Studies have found that microglia also express a variety of neurotransmitter receptors, such as glutamate receptors (iGluRs and mGluRs), GABA receptors, purinergic receptors, adenosine receptors, cholinergic receptors, adrenergic receptors, dopamine receptors, opioid receptors, and neuropeptide receptors. Microglia express various neurotransmitter receptors, which regulate activation, phagocytosis, and polarization, mediating bidirectional communication between neurons and microglia.⁸³ Among them, A_2A receptor (A_2AR) exists and plays an important role in neurodegeneration, affecting microglia and neuroinflammation. Depending on different pathological environments and cell types, the receptor has a bidirectional dual effect on regulating neuroinflammation. For example, in spinal cord injury, A_2AR activation may exert a protective effect by inhibiting neuroinflammation; however, in later stages, the condition may worsen.⁸⁴ The adenosine A2A receptor and cannabinoid CB2 receptor (CB2R) interact with each other, mainly regulated through the PKA and CREB pathways. This interaction promotes the transformation of microglia to the M2 type and inhibits neuroinflammation.^85,86

The antagonism of A_2AR may promote the neuroprotective effects of microglia by enhancing CB2R signaling, thereby delaying the progression of neurodegenerative diseases such as AD.⁸⁷ Neurotransmitter receptor activation modulates microglial polarization, inhibits M1 polarization, and protects neurons. Under pathological conditions, A_2AR can damage neurons through neuroinflammation, and it can also act directly on neurons. In the presence of oxidative stress, the structure and function of neurons are disrupted. The receptor inhibits oxidative stress through pathways such as NF-κB, thereby reducing neuronal damage and potentially reversing AD.⁸⁸

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal and differentiation capabilities. They can horizontally differentiate into cells of non-mesodermal origin, such as glial cells and neurons, making them an ideal source for replacing lost cells in neurodegenerative diseases. MSCs are easy to collect, isolate, and cultivate; they have low immunogenicity and exhibit immunomodulatory functions, demonstrating promising application prospects in treatment.

Studies have shown that MSCs can promote macrophage polarization towards the M2 type through cytokines such as IL-13 and IL-4, indicating their anti-inflammatory effects and important role in inflammatory diseases. In the context of AD, MSCs have been found to reconstruct the neural microenvironment, promote neuronal growth, and alleviate or reverse nerve damage. Additionally, MSCs can activate endogenous anti-inflammatory factors in microglia, promote Aβ clearance, and improve memory and cognitive function.^89,90

Monoclonal antibodies

Monoclonal antibodies (MAbs) are highly specific antibodies produced through cloning technology, designed to target specific antigens or receptors. With advancements in biotechnology, the affinity, stability, and targeting capabilities of MAbs are expected to continue improving.⁹¹ Monoclonal antibodies play an important role in the treatment of AD: (A) Amyloid-β targeted therapies include agents such as aducanumab, lecanemab, and donanemab. Aducanumab has demonstrated a significant effect in slowing cognitive decline, while lecanemab and donanemab are currently in clinical trials. It is worth noting that the efficacy and safety of aducanumab are highly controversial in clinical practice and have been found to have multiple serious side effects, even leading to patient death and harm. Therefore, it is called for a more comprehensive evaluation and monitoring or a ban on the widespread clinical use of similar drugs before their approval; (B) Tau protein-targeted therapies encompass drugs like gosuranemab, tilavonemab, and zagotenemab, which are also in the clinical trial phase. Additionally, MAbs targeting phosphorylated tau, including semorinemab and BIIB076, are under active investigation; (C) Targeted therapies for neuroinflammation focus on TREM2, a transmembrane receptor on microglia that influences their function and activity. Mutations in the TREM2 gene and interactions with ligands can impact the pathology of Aβ plaques and tau proteins in the brains of patients, highlighting its critical role in AD pathology. Currently, TREM2 and other inflammatory factors are being studied as potential therapeutic targets. Agonistic MAbs like AL002 and DNL919 have entered clinical trials, aiming to clear Aβ and promote the transformation of microglia to the M2 phenotype, enhancing their phagocytic function to reduce neuroinflammation and potentially reverse or delay the pathological changes associated with AD.^92–94

Nanoparticles

Nanoparticles refer to tiny particles ranging in size from 1 to 100 nanometers in one dimension. Due to their advantageous physical and chemical properties, such as small size and large specific surface area, nanoparticles are widely utilized in biomedical applications.⁹⁵ Nanoparticles can be classified into two main categories: inorganic and organic. Inorganic nanoparticles include gold nanoparticles (AuNPs), iron oxide nanoparticles (IONPs), and silicon dioxide nanoparticles (SiO2NPs), while organic nanoparticles encompass liposomes, solid lipid nanoparticles (SLNs), nanoemulsions, polymer nanoparticles, and dendrimers.⁹⁶ In the context of neurodegenerative diseases, nanoparticles represent a significant therapeutic strategy, particularly for AD. They can effectively cross the blood-brain barrier to deliver neuroprotective peptides, such as NAP, or neurotrophic factors, like NGF. Additionally, they play a role in reducing amyloid-β load and improving cognitive function.⁹⁷

NP-delivered anti-inflammatory drugs or regulatory molecules modulate microglial activation and inflammatory mediator release, alleviating neuroinflammation and protecting neurons. For example, TPP-MoS2 quantum dots convert M1 to M2 microglia and clear ROS, while PDA@K NPs alleviate neuroinflammation and promote M2 polarization.^98–100 AuNPs have unique physical properties that can affect the activity of immune cells, thereby regulating neuroinflammation. When acting on microglia, AuNPs can inhibit M1 polarization of microglia through signaling pathways such as NF-κB and MAPK, reducing neuroinflammation. In addition, they have antioxidant effects, clearing ROS, reducing neuroinflammation caused by oxidative stress, and reversing neuronal damage.¹⁰¹ Nanotechnology offers precision modulation of microglial function, providing new strategies for AD treatment, However, in clinical practice, further exploration is needed regarding its safety and the toxic side effects of nanoparticles.

Gene therapy

Gene therapy refers to a method of treating diseases by transferring genetic material (DNA or RNA) into a patient's cells, thereby promoting the restoration of normal cellular function by repairing or replacing defective genes. This innovative approach plays an important role in various diseases, offering fundamental treatment solutions with high efficacy. However, it also faces challenges and controversies regarding safety and ethics. In the context of neurodegenerative diseases, particularly those involving neuroinflammation, gene therapy is a promising strategy. It can directly protect nerve growth factors, prevent further damage to neurons, and promote neuronal recovery and growth. Even in cases where the condition cannot be fully reversed, gene therapy may help control disease progression.^102,103 Gene therapy for neurodegeneration mainly involves techniques such as gene replacement therapy, gene suppression or splicing, and nucleic acid editing methods like CRISPR.^104,105 For example CRISPR/Cas9 technology can edit inflammation-related genes, inhibiting microglial inflammation and mitigating AD-related neurodamage.¹⁰⁶

Each therapeutic strategy targeting neuroinflammation in AD has its unique mechanisms and challenges. Further research in the future should focus on optimizing their delivery systems and validating their effectiveness and safety through clinical trials. By doing so, we can select effective treatment options to delay disease progression and improve survival rates.

Conclusion

The polarization of microglia plays a crucial role in the pathogenesis of AD, where the pro-inflammatory M1 phenotype exacerbates neuroinflammation and neurodegeneration, while the anti-inflammatory M2 phenotype promotes tissue repair and neuroprotection. By developing strategies to polarize microglia in AD to a beneficial M2 phenotype and reduce neuroinflammation, we can optimize treatment interventions for AD. The future prospects include exploring combination therapies, identifying new targets, and conducting clinical trials to evaluate the efficacy and safety of these interventions in AD patients.

Footnotes

ORCID iDs

Xinmao Yang

Jie Wang

Xiaotao Jia

Yaqian Yang

Yanfang Pan

Author contributions

Xinmao Yang (Writing – original draft); Jie Wang (Supervision; Writing – original draft); Xiaotao Jia (Methodology; Writing – original draft); Yaqian Yang (Supervision); Yan Fang (Conceptualization); Xiaoping Ying (Supervision); Hong Li (Supervision); Meiqian Zhang (Investigation; Supervision); Jing Wei (Supervision; Validation); Yanfang Pan (Conceptualization; Funding acquisition; Writing – review & editing).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the National Science Foundation of PR China (81703842), Key Research and Development Program of Shaanxi Province of PR China (2024SF-YBXM-147; 2023-YBSF-394), Traditional Chinese Medicine Scientific Research Projects of Shaanxi Province, PR China (SZY-KJCYC-2023-031) and Research Project at Shaanxi University of Traditional Chinese Medicine (2023GP13).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Knopman

Amieva

Petersen

, et al. Alzheimer disease. Nat Rev Dis Primers 2021; 7: 33.

Leng

Edison

. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 2021; 17: 157–172.

Boreland

, et al. Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology. Stem Cell Reports 2021; 16: 1923–1937.

Jiang

Deng

, et al. Modulators of microglia activation and polarization in ischemic stroke (review). Mol Med Rep 2020; 21: 2006–2018.

Kwon

Koh

. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 2020; 9: 42.

Chai

Gao

, et al. Molecular mechanism of the protective effects of M2 microglia on neurons: a review focused on exosomes and secretory proteins. Neurochem Res 2022; 47: 3556–3564.

Yao

. Microglial polarization: novel therapeutic mechanism against Alzheimer's disease. Inflammopharmacology 2020; 28: 95–110.

Dhapola

Hota

Sarma

, et al. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer's disease. Inflammopharmacology 2021; 29: 1669–1681.

Ren

Zhang

, et al. Microglial polarization in TBI: signaling pathways and influencing pharmaceuticals. Front Aging Neurosci 2022; 14: 901117.

10.

Tanaka

Sackett

Zhang

. Endocannabinoid modulation of microglial phenotypes in neuropathology. Front Neurol 2020; 11: 87.

11.

Shui

Sun

, et al. Microglial phenotypic transition: signaling pathways and influencing modulators involved in regulation in central nervous system diseases. Front Cell Neurosci 2021; 15: 736310.

12.

Isik

Yeman Kiyak

Akbayir

, et al. Microglia mediated neuroinflammation in Parkinson's disease. Cells 2023; 12: 1012.

13.

Guo

Wang

Yin

. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci 2022; 14: 815347.

14.

Leak

Shi

, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 2015; 11: 56–64.

15.

Kulkarni

Cruz-Martins

Kumar

. Microglia in Alzheimer's disease: an unprecedented opportunity as prospective drug target. Mol Neurobiol 2022; 59: 2678–2693.

16.

Merighi

Nigro

Travagli

, et al. Microglia and Alzheimer's disease. Int J Mol Sci 2022; 23: 12990.

17.

Ogunmokun

Dewanjee

Chakraborty

, et al. The potential role of cytokines and growth factors in the pathogenesis of Alzheimer's disease. Cells 2021; 10: 2790.

18.

Momtazmanesh

Perry

Rezaei

. Toll-like receptors in Alzheimer's disease. J Neuroimmunol 2020; 348: 577362.

19.

Fan

Bai

Yang

, et al. The key roles of reactive oxygen species in microglial inflammatory activation: regulation by endogenous antioxidant system and exogenous sulfur-containing compounds. Eur J Pharmacol 2023; 956: 175966.

20.

Cai

Pei

. Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response. J Neuroinflammation 2017; 14: 63.

21.

Zhang

Yuan

, et al. Biomaterial-supported MSC transplantation enhances cell-cell communication for spinal cord injury. Stem Cell Res Ther 2021; 12: 36.

22.

Rajendran

Paolicelli

. Microglia-mediated synapse loss in Alzheimer's disease. J Neurosci 2018; 38: 2911–2919.

23.

Yang

Liu

Yang

, et al. Platycodigenin as potential drug candidate for Alzheimer's disease via modulating microglial polarization and neurite regeneration. Molecules 2019; 24: 3207.

24.

Yang

Kuboyama

Tohda

. Naringenin promotes microglial M2 polarization and Abeta degradation enzyme expression. Phytother Res 2019; 33: 1114–1121.

25.

Jiang

Wei

, et al. Phillyrin prevents neuroinflammation-induced blood-brain barrier damage following traumatic brain injury via altering microglial polarization. Front Pharmacol 2021; 12: 719823.

26.

Amanollahi

Jameie

Heidari

, et al. The dialogue between neuroinflammation and adult neurogenesis: mechanisms involved and alterations in neurological diseases. Mol Neurobiol 2023; 60: 923–959.

27.

Zhou

Chen

. TSPO Modulates IL-4-induced microglia/macrophage M2 polarization via PPAR-gamma pathway. J Mol Neurosci 2020; 70: 542–549.

28.

Qin

Wang

. Novel balance mechanism participates in stem cell therapy to alleviate neuropathology and cognitive impairment in animal models with Alzheimer's disease. Cells 2021; 10: 2757.

29.

Javanmehr

Saleki

Alijanizadeh

, et al. Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases. J Neuroinflammation 2022; 19: 273.

30.

Wang

Wen

. The roles of RhoA/ROCK/NF-kappaB pathway in microglia polarization following ischemic stroke. J Neuroimmune Pharmacol 2024; 19: 19.

31.

Abusaliya

Bhosale

Kim

, et al. Prunetinoside inhibits lipopolysaccharide-provoked inflammatory response via suppressing NF-kappaB and activating the JNK-mediated signaling pathway in RAW264.7 macrophage cells. Int J Mol Sci 2022; 23: 5442.

32.

Wang

Baldwin

Jr . Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J Biol Chem 1998; 273: 29411–29416.

33.

Wang

, et al. Macrophage polarization modulated by NF-kappaB in polylactide membranes-treated peritendinous adhesion. Small 2022; 18: e2104112.

34.

Lawrence

. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009; 1: a001651.

35.

Lin

Zhang

, et al. Targeting NF-kappaB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther 2020; 5: 209.

36.

Tian

Liang

Shi

, et al. Exosomal CXCL14 contributes to M2 macrophage polarization through NF-kappaB signaling in prostate cancer. Oxid Med Cell Longev 2022; 2022: 7616696.

37.

Wang

Palomares

Parobchak

, et al. Glucocorticoid receptor signaling contributes to constitutive activation of the noncanonical NF-kappaB pathway in term human placenta. Mol Endocrinol 2013; 27: 203–211.

38.

Yin

Ren

Huang

, et al. Exploration about changes of IL-10, NF-kappaB and MMP-3 in a rat model of cervical spondylosis. Mol Immunol 2018; 93: 184–188.

39.

Zong

Zhu

Zhang

, et al. SR-A1 suppresses colon inflammation and tumorigenesis through negative regulation of NF-kappaB signaling. Biochem Pharmacol 2018; 154: 335–343.

40.

Lai

Chang

Hsieh

. Signal transduction pathways of acupuncture for treating some nervous system diseases. Evid Based Complement Alternat Med 2019; 2019: 2909632.

41.

Srinivasan

Walker

. Circadian clock, glucocorticoids and NF-kappaB signaling in neuroinflammation- implicating glucocorticoid induced leucine zipper as a molecular link. ASN Neuro 2022; 14: 17590914221120190.

42.

Parra-Damas

Saura

. Synapse-to-nucleus signaling in neurodegenerative and neuropsychiatric disorders. Biol Psychiatry 2019; 86: 87–96.

43.

Coutinho-Wolino

Almeida

Mafra

, et al. Bioactive compounds modulating Toll-like 4 receptor (TLR4)-mediated inflammation: pathways involved and future perspectives. Nutr Res 2022; 107: 96–116.

44.

Sun

Motolani

Campos

, et al. The pivotal role of NF-kB in the pathogenesis and therapeutics of Alzheimer's disease. Int J Mol Sci 2022; 23: 8972.

45.

Fitzgerald

Kagan

. Toll-like receptors and the control of immunity. Cell 2020; 180: 1044–1066.

46.

Heidari

Yazdanpanah

Rezaei

. The role of Toll-like receptors and neuroinflammation in Parkinson's disease. J Neuroinflammation 2022; 19: 135.

47.

Talapphet

Palanisamy

, et al. Polysaccharide extracted from Taraxacum platycarpum root exerts immunomodulatory activity via MAPK and NF-kappaB pathways in RAW264.7 cells. J Ethnopharmacol 2021; 281: 114519.

48.

Huang

Zhang

Haneke

, et al. Glial cell line-derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia-mediated glioma progression. J Neurosci Res 2021; 99: 1048–1063.

49.

Song

Niu

Zhang

, et al. Purple sweet potato polysaccharide exerting an anti-inflammatory effect via a TLR-mediated pathway by regulating polarization and inhibiting the inflammasome activation. J Agric Food Chem 2024; 72: 2165–2177.

50.

Yuan

Shen

Lin

, et al. Scavenger receptor SRA attenuates TLR4-induced microglia activation in intracerebral hemorrhage. J Neuroimmunol 2015; 289: 87–92.

51.

Pawelec

Ziemka-Nalecz

Sypecka

, et al. The impact of the CX3CL1/CX3CR1 axis in neurological disorders. Cells 2020; 9: 2277.

52.

Wolf

Yona

Kim

, et al. Microglia, seen from the CX3CR1 angle. Front Cell Neurosci 2013; 7: 26.

53.

Hou

Chen

Grajales-Reyes

, et al. TREM2 Dependent and independent functions of microglia in Alzheimer's disease. Mol Neurodegener 2022; 17: 84.

54.

Wang

Lin

Wang

, et al. TREM2 Ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer's disease mice. Aging (Albany NY) 2020; 12: 20862–20879.

55.

Wang

, et al. The versatile role of TREM2 in regulating of microglia fate in the ischemic stroke. Int Immunopharmacol 2022; 109: 108733.

56.

Wang

Yang

Zhang

, et al. TREM2 Overexpression attenuates cognitive deficits in experimental models of vascular dementia. Neural Plast 2020; 2020: 8834275.

57.

Tagliatti

Desiato

Mancinelli

, et al. Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development. Immunity 2024; 57: 86–105.e109.

58.

Gartner

Bitar

Zipp

, et al. Interleukin-4 as a therapeutic target. Pharmacol Ther 2023; 242: 108348.

59.

Iwaszko

Bialy

Bogunia-Kubik

. Significance of interleukin (IL)-4 and IL-13 in inflammatory arthritis. Cells 2021; 10: 3000.

60.

Liu

Taso

Wang

, et al. Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions. Hum Mol Genet 2020; 29: 3224–3248.

61.

Schwager

Bompard

Raederstorff

, et al. Resveratrol and omega-3 PUFAs promote human macrophage differentiation and function. Biomedicines 2022; 10: 1524.

62.

Skat-Rordam

Hojland Ipsen

Lykkesfeldt

, et al. A role of peroxisome proliferator-activated receptor gamma in non-alcoholic fatty liver disease. Basic Clin Pharmacol Toxicol 2019; 124: 528–537.

63.

Wang

Feng

, et al. The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPARgamma. Adv Sci (Weinh) 2021; 8: 2100209.

64.

Lin

Meng

Song

, et al. Peroxisome proliferator-activator receptor gamma and psoriasis, molecular and cellular biochemistry. Mol Cell Biochem 2022; 477: 1905–1920.

65.

Lecca

Janda

Mulas

, et al. Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARgamma agonist MDG548 in Parkinson's disease models. Br J Pharmacol 2018; 175: 3298–3314.

66.

Marechal

Laviolette

Rodrigue-Way

, et al. The CD36-PPARgamma pathway in metabolic disorders. Int J Mol Sci 2018; 19: 1529.

67.

Liu

Wang

Zhang

, et al. WISP1 Alleviates lipid deposition in macrophages via the PPARgamma/CD36 pathway in the plaque formation of atherosclerosis. J Cell Mol Med 2020; 24: 11729–11741.

68.

Ding

Kang

Liu

, et al. The protective effects of peroxisome proliferator-activated receptor gamma in cerebral ischemia-reperfusion injury. Front Neurol 2020; 11: 588516.

69.

Korbecki

Bobinski

Dutka

. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm Res 2019; 68: 443–458.

70.

Kim

Park

Won

, et al. Repression of PPARgamma reduces the ABCG2-mediated efflux activity of M2 macrophages. Int J Biochem Cell Biol 2021; 130: 105895.

71.

Panchal

Prince Sabina

. Non-steroidal anti-inflammatory drugs (NSAIDs): a current insight into its molecular mechanism eliciting organ toxicities. Food Chem Toxicol 2023; 172: 113598.

72.

Stopschinski

Weideman

McMahan

, et al. Microglia as a cellular target of diclofenac therapy in Alzheimer's disease. Ther Adv Neurol Disord 2023; 16: 17562864231156674.

73.

Rogers

. The inflammatory response in Alzheimer's disease. J Periodontol 2008; 79: 1535–1543.

74.

Mendelsohn

Larrick

. Metabolic reprogramming rejuvenates aged myeloid cells restoring cognition. Rejuvenation Res 2021; 24: 65–67.

75.

Shimba

Ikuta

. Control of immunity by glucocorticoids in health and disease. Semin Immunopathol 2020; 42: 669–680.

76.

De Nicola

Meyer

Guennoun

, et al. Insights into the therapeutic potential of glucocorticoid receptor modulators for neurodegenerative diseases. Int J Mol Sci 2020; 21: 2137.

77.

Hisaoka-Nakashima

Azuma

Ishikawa

, et al. Corticosterone induces HMGB1 release in primary cultured rat cortical astrocytes: involvement of pannexin-1 and P2X7 receptor-dependent mechanisms. Cells 2020; 9: 1068.

78.

Dubey

Singh

. Antioxidants: an approach for restricting oxidative stress induced neurodegeneration in Alzheimer's disease. Inflammopharmacology 2023; 31: 717–730.

79.

Mani

Dubey

Lai

, et al. Oxidative stress and natural antioxidants: back and forth in the neurological mechanisms of Alzheimer's disease. J Alzheimers Dis 2023; 96: 877–912.

80.

Zhang

Zheng

Luo

, et al. Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/ TLR4/ NF-kappaB pathways in BV2 cells. Mol Immunol 2019; 116: 29–37.

81.

Mir

Shah

Mohi-Ud-Din

, et al. Natural anti-inflammatory compounds as drug candidates in Alzheimer's disease. Curr Med Chem 2021; 28: 4799–4825.

82.

Huang

, et al. Signaling mechanisms underlying inhibition of neuroinflammation by resveratrol in neurodegenerative diseases. J Nutr Biochem 2021; 88: 108552.

83.

Liu

Leak

. Neurotransmitter receptors on microglia. Stroke Vasc Neurol 2016; 1: 52–58.

84.

Dai

Zhou

. Adenosine 2A receptor: a crucial neuromodulator with bidirectional effect in neuroinflammation and brain injury. Rev Neurosci 2011; 22: 231–239.

85.

Tao

Jiang

, et al. Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model. Brain Behav Immun 2016; 58: 118–129.

86.

Lin

Yihao

Zhou

, et al. Inflammatory regulation by driving microglial M2 polarization: neuroprotective effects of cannabinoid receptor-2 activation in intracerebral hemorrhage. Front Immunol 2017; 8: 112.

87.

Franco

Reyes-Resina

Aguinaga

, et al. Potentiation of cannabinoid signaling in microglia by adenosine A(2A) receptor antagonists. Glia 2019; 67: 2410–2423.

88.

Cunha

. How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 2016; 139: 1019–1055.

89.

Ankrum

Ong

Karp

. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 2014; 32: 252–260.

90.

Yao

Zhou

Zhu

, et al. Mesenchymal stem cells: a potential therapeutic strategy for neurodegenerative diseases. Eur Neurol 2020; 83: 235–241.

91.

Mould

Meibohm

. Drug development of therapeutic monoclonal antibodies. BioDrugs 2016; 30: 275–293.

92.

Guo

Yan

Zhang

, et al. Passive immunotherapy for Alzheimer's disease. Ageing Res Rev 2024; 94: 102192.

93.

Tipton

. Updates on pharmacological treatment for Alzheimer's disease: response to Letter to the Editors. Neurol Neurochir Pol 2024; 58: 142–143.

94.

Kulkarni

Kumar

Cruz-Martins

, et al. Role of TREM2 in Alzheimer's disease: a long road ahead. Mol Neurobiol 2021; 58: 5239–5252.

95.

Whitehouse

Saini

. Making the case for the accelerated withdrawal of aducanumab. J Alzheimers Dis 2022; 87: 999–1001.

96.

Najahi-Missaoui

Arnold

Cummings

. Safe nanoparticles: are we there yet? Int J Mol Sci 2020; 22: 385.

97.

Zhu

, et al. Nanoparticles: a hope for the treatment of inflammation in CNS. Front Pharmacol 2021; 12: 683935.

98.

Saraiva

Praca

Ferreira

, et al. Nanoparticle-mediated brain drug delivery: overcoming blood-brain barrier to treat neurodegenerative diseases. J Control Release 2016; 235: 34–47.

99.

Ren

Zhou

, et al. Mitochondria-targeted TPP-MoS(2) with dual enzyme activity provides efficient neuroprotection through M1/M2 microglial polarization in an Alzheimer's disease model. Biomaterials 2020; 232: 119752.

100.

Huang

Jiang

Xia

, et al. Pathological BBB crossing melanin-like nanoparticles as metal-ion chelators and neuroinflammation regulators against Alzheimer's disease. Research (Wash D C) 2023; 6: 0180.

101.

Srivastava

Ahmad

Khare

. Alzheimer's disease and its treatment by different approaches: a review. Eur J Med Chem 2021; 216: 113320.

102.

Chiang

Yang

Nicol

CJB

, et al. Gold nanoparticles in neurological diseases: a review of neuroprotection. Int J Mol Sci 2024; 25: 2360.

103.

Tang

. Gene therapy: a double-edged sword with great powers. Mol Cell Biochem 2020; 474: 73–81.

104.

Sudhakar

Richardson

. Gene therapy for neurodegenerative diseases. Neurotherapeutics 2019; 16: 166–175.

105.

Eichler

Brown

Jr . Gene therapy for neurologic disorders. Neurotherapeutics 2024; 21: e00453.

106.

Cai

, et al. Application of CRISPR/Cas9 in Alzheimer's disease. Front Neurosci 2021; 15: 803894.