Research Progress of Targeting Neuro-Immune Inflammation in the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system characterized by extracellular senile plaques and the formation of intracellular neurofibrillary tangles. The accumulation of toxic beta-amyloid (A β ) induces the overproduction of reactive oxygen species (ROS), nitric oxide (NO) and pro-inflammatory cytokines. Accumulating studies suggest that neuroinflammatory mechanism plays an important role in the occurrence and development of AD. Microglia, astrocytes, macrophages, mast cells and T cells are involved in the pathogenesis of AD through neuroimmune mechanisms and inflammatory reactions. In recent years, many new drugs have been developed for the treatment of AD targeting neuroimmune and inflammatory mechanisms. Although some drugs failed in the Ⅲ phase of clinical trial, they made sense on subsequent research. This paper mainly discusses the positive effects on AD according to immunotherapy, anti-inflammatory treatment and regulation of immune inflammation by traditional Chinese medicine, in order to benefit for prevention or treatment of AD in the future.


Introduction
Alzheimer's disease (AD), which is the most common type of dementia, is characterized by senile plaques formed by abnormal aggregation of Aβ and neurofibrillary tangles consisted of hyperphosphorylated Tau.In addition, there are some other factors involved in the development of AD, like apolipoprotein, human metabolic, gene, cholinergic system, estrogen, immunoglobulin-like receptor B (Pir B), thrombin, several cardiovascular and cerebrovascular diseases [1].In recent years, the role of neuroimmune inflammation in the pathophysiology and related treatment of the disease has aroused great interest.On one hand, Aβ, an antimicrobial peptide (AMP), play a role in the normal innate immune system [2].On the other hand, congenital immune-mediated inflammation, can spread AD neurodegeneration.Peripheral immune response plays an important effect in the later stages of AD pathophysiology when dementia is in progress [3].Moreover, Gjoneska E et al. [4] found that the immune response related genes and regulatory regions of AD mice were upregulated, and AD related genetic variation was related to the immune process.AD variant genes were significantly enriched in immune system related pathways.AD single nucleotide polymorphisms have shown significant DNA enzyme enrichment in immune cells, including four types of B cells (the first four significant signals), CD14 + T and CD34 + T cells [5].Therefore, a well-functioned immune response and endocy-tosis pathway may be involved in the neuroprotective effect of AD [6].
The role of neuroimmune inflammation in AD is inseparable from immune cells, including microglia, astrocyte, macrophage and etc. Different types of cells serve as different roles in the development of AD (Fig. 1).In this review, we mainly discuss the immune cells and their roles in AD, as well as the treatment of AD based on neuroimmune inflammation.Based on the above content, we aim to inspire new ideas for AD treatment.

Microglia
Microglia, the inherent immune cells with features of multi-synapses and plasticity in the central nervous system, plays an extremely important role in AD physiological process.Neuroimmune inflammation mediated by microglia activation is an important pathological feature in neurodegenerative diseases.After stimulated by ischemia, infection and injury, microglia can be activated and divided into M1 type and M2 type polarization states.M1 microglia expresses CD16, CD32 and CD86, while M2 microglia expresses CD206, Arg1 and neurotrophic factor insulin-like growth factor 1 (IGF-1) [7].M1 type microglia has proinflammatory function through secreting pro-inflammatory factors.Under the induction of lipopolysaccharide (LPS) and interferon γ (IFN-γ), M1 release a large amount of NO, tumor necrosis factor α (TNF-α), interleukin-1 β (IL-1β), interleukin 6 (IL-6), superoxide.These pro-inflammatory factors and toxic substances can accelerate the inflammatory response, and eventually leading to neuronal damage.M2 type microglia secretes anti-inflammatory cytokines, such as transforming growth factor β (TGF-β), IL-4, IL-10 and vascular endothelial growth factor (VEGF).M2 plays an anti-inflammatory role by blocking NO production, inhibiting nuclear factor κB (NF-κB) signaling pathway, and upregulating arginine 1 (Arg1), thereby promoting regeneration and repair of neurons [8].
In AD, microglia-mediated chronic inflammation and oxidative stress responses lead to neurological tissue damage.Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor which is primarily expressed by microglia and regulates microglia cytokine production and phagocytosis.TREM2 plays a key role in the development and progression of AD, and its outer domain can be transformed by proteolysis into a soluble variant (sTREM2).sTREM2 can be detected in cerebrospinal fluid (CSF) [9].Decreased TREM2 function is associated with increased risks of AD, Parhizkar S et al. [10] found an increased dose of amyloid plaque seeding in the absence of functional TREM2, and the aggregation of microglia around newly seeded spots was reduced, and plaque associated apolipoprotein E (ApoE) also decreased.Despite ApoE reduction, early amyloidogenesis is accelerated due to phagocytes' clearance rate of amyloid seeds being reduced.Loss of TREM2 also reduces microglia survival, damages phagocytosis of key substrates including APOE, inhibits SDF-1α/CXCR4-mediated chemotaxis, and ultimately leads to impaired response to Aβ in vivo [11].On the contrary, overexpression of TREM2 in microglia can promote M2 polarization and reduce the inflammatory response of M1 microglia through the JAK/STAT/SOCS signaling pathway.TREM2 is an important factor in the transition of microglia from M1 phenotype to M2 phenotype [12].
Human genetic data have found that variations in TREM2 and PLCG2 gene expressed in microglia, which suggests that microglia dysfunction can contribute to the pathology of AD [13].Coding variations in TREM2 are associated with late-onset AD.Finelli D et al. [14] genotyped samples from 474 AD patients and 608 healthy controls from the North West of England and found a significant association T allele of the variant TREM2 RS75932628 with AD.In addition, R47H variants in TREM2 receptors are an important risk factor for AD [15].The APOE4 genotype have been proved to impair phagocytosis, migration, and metabolic activity of human microglia-like cells (iMGLs) [16].AD-associated SORL1 and TREM2 mutations also impair Aβ uptake by ESC-derived microglia (hMGL) in vitro in an ApoE-dependent manner and attenuate Aβ clearance in the brain of AD mouse models [17].
Accumulating evidences show neuroinflammation contributes to the pathogenesis of AD, which leads to synaptic loss and cognitive decline.Hong S et al. [18] revealed that complement is associated with microgliamediated early synaptic loss in AD model mouse.C1q is the initiation protein of the classical complement cascade, which increases before apparent plaque deposition.Inhibition of C1q, C3 or microglia complement receptor CR3 can reduce the number of phagocytes and the degree of early synaptic loss.Thus, excessive activation of complement dependent pathways and microglia mediates AD synaptic loss.CD14 is a receptor involved in regulating the inflammatory response of microglia caused by bacterial infection or lipopolysaccharide stimulation [19].Martin E et al. [20] showed that CD14 and CD36 involved in phagocytosis, were up-regulated, and the contents of proinflammatory mediators IL-1β, P40, inducible nitric oxide synthase (iNOS), CCL-3, CCL-4 and CXCL-1 were higher in AD model.

Monocytes/Macrophages
In AD, Aβ activates microglia and its related neuroinflammation, which leads to increased permeability of the blood-brain barrier (BBB) and recruitment of peripheral macrophages into the brain [21].Activated macrophages can differentiate into M1 and M2 types and involve in regulation of neuroinflammation.
Stalk associated RH domain interacting protein (SHARPIN) is a key regulator of inflammatory response.SHARPIN acts as an obligate regulator of Aβ phagocytosis and inflammation in macrophages.THP-1 macrophages' SHARPIN expression stimulated by Aβ can promote Aβ phagocytosis and the expression of pro-inflammatory markers.In addition, Aβ-stimulated SHARPIN promotes the death of differentiated SHSY5Y neurons.In THP-1 macrophages, there was a closely positive correlation between plasma Aβ42 level in mild cognitive impairment patients and SHARPIN expression in peripheral blood monocytes of AD [22].In addition, the presence of ApoEε4 allele and oxidative stress can also affect the phagocytosis efficiency of macrophages [23].Monocytes are involved in the development of AD.They can uptake of Aβ1-42, which decline with age, and reduce the expression of Toll-like receptor 2 (TLR2) associated with Aβ uptake [24].In the meantime, Lim C et al. [25] have found that monocytes promote innate immune responses and play an underlying role in inflammatory initiation of sporadic/late-onset AD.

Mast Cells
Mast cells in brain are associated with neurodegenerative diseases such as AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).Girolamo F et al. [26] found that many mast cells gathered around Aβ plaques in the brain of AD patients.The gathering of mast cells may be induced by mast cell chemoattractant produced by glial cells stimulated by neuroinflammation.Activated mast cells degranulate rapidly through CD47/β1 integrin membrane complex, release inflammatory mediators to aggravate AD neuroinflammation.Meanwhile, inflammatory mediators activate microglia to further expand inflammation and promote the occurrence and development of AD [26].

T Cells
The clearance of Aβ in peripheral blood is closely related to immune cells, especially T cells.The function of peripheral immune cells and their oxidative stress state may be a good early peripheral blood marker for the preclinical and progression of AD [27].Lueg G et al. [28] found that specific adaptive immune responses are mediated by CD8 + T cells in AD, and the level of activated CD8 + T cells is correlated with clinical and structural markers of AD pathology.
Ferretti MT et al. [29] found an increased number of T cells infiltrating in brain regions with amyloid load in transgenic AD mouse models.This suggests that brain amyloidosis promotes T-cell infiltration and activation.The inability of brain immune surveillance to coordinate protective immune responses to Aβ may contribute to amyloid accumulation.St-amour I et al. [30] also found that activation of B lymphocytes, T lymphocytes and serum IL-2 level increased in AD mice.Helper T lymphocytes Th17 were polarized by increased concentrations of IL-17 and granulocyte-macrophage cluster stimulating factors.In addition, not only CD4 + and CD8 + T cell reactivity was increased in AD, but also reactive memory T cells were produced [31].

Neutrophils
Changes in the BBB facilitate the exchange of inflammatory mediators and immune cells between the brain and the periphery, and differences in polymorphic nuclear neutrophils' (PMN) responsiveness to pathological attacks induces to impaired responses in AD development [32].Park J et al. [33] found that microglia activated by Aβ can produce neutrophil chemical inducer, including IL6, IL8, CCL2, CCL3/4, and CCL5, which induce neutrophil aggregation.Interaction between microglia and neutrophil can lead to the production of inflammatory mediators (such as MIF and IL2) and speed up the progression of AD neuroinflammation.A recent study has shown that neutrophils increase in AD brain and AD mouse model.In the AD model, a large number of neutrophils infiltrate around the plaque, Table 1.The role of various immune cells in AD.

Astrocytes
Aβ activates astrocyte NF-κB, leading to the release of complement C3.Astrocyte and microglia can interact to induce microglia polarization and aggravate Aβ pathology and neuroinflammation [35,36].and the extracellular enzyme myeloperoxidase (MPO) is deposited in the blood vessels.These vascular changes drive neutrophil adhesion and neutrophil extracellular traps (NETs), ultimately leading to oxidative stress and cognitive impairment [34].

Astrocytes
Astrocytes are the most widely distributed and the largest glia cells in the body.Astrocytes have protuberances that provide the function of supporting and separating nerve cells, and participate in the formation of BBB.In recent years, there have been many studies on the role of astrocytes in AD.Lian H et al. [35] have found that NF-κB hyperactivation and C3 elevation in astrocytes aggravate Aβ pathology and neuroinflammation in AD mice, while C3aR antagonist (C3aRA) ameliorate plaque burden and microglia hyperplasia.Aβ activates NF-κB in astrocytes and releases complement C3, which then acts on neuronal C3a receptor (C3aR), ultimately affecting dendritic morphology and cognitive function.Astrocytes and microglia can interact to induce microglia polarization and proliferation which can alter cognitive function and affect Aβ phagocytosis [36].The correlation between astrocytes and microglia may provide new insight for targeted therapy of AD.

Immunotherapy
Autoimmune characteristics are associated with AD.Autoantibodies against receptor for advanced glycation end products (RAGE) and cytotoxic Aβ42 were present in plasma samples from patients with AD [37].Persistent viral infection and age-related progressive decline in immunity have played a key role among the environmental factors associated with AD.The expression profile of innate antimicrobial genes is impaired in the brain of AD patients, and individual gene composition (such as positive APOE ε4 and IRF7A alleles) may affect the brain immune efficiency [38].Gericke C et al. [39] have found that Aβ deposition is accompanied by a marked reduction in MHC II levels on brain antigen-presenting cells (APCs).Furthermore, Aβ 1−42 can inhibit antigen presentation by altering the transcription of key immune mediators in dendritic cells.Therefore, impaired immune surveillance in the brain may be one of the factors that promote the spread of Aβ and tau in AD.
AD patients show severe cognitive deficits accompanied by increased brain aggregation deposits of Aβ.Modulation of Aβ homeostasis has been suggested as a therapeutic approach for AD patients.It has been shown that active and passive immunization with Aβ (Table 2) can restore different forms of Aβ balance in the brain, leading to improvement of cognitive function in mouse models of AD.

Active Immunity
Active immunotherapy targeting Aβ is the most promising strategy for the prevention or treatment of AD.Active immunotherapy is designed to induce specific Aβ antibodies, which can reduce the level of Aβ in the central nervous system of AD patients.AN-1792, the first clinical trial based on a full-length Aβ42 vaccine, showed that a safe and effective AD vaccine should induce high titers of anti-Aβ antibodies and without activating harmful self-reactive T cells [40].Davtyan H et al. [41] found that Lu AF20513 induced a powerful "non-self" T cell response and the production of anti-Aβ antibodies, and reduced AD like lesions in the mouse brain and simultaneously didn't induce microglial activation.In addition, antibodies which anti-Aβ and anti-influenza have a strong therapeutic effect by using chimeric viruses synthesized from two influenza viruses as routine inactivated vaccines [42].
Although Aβ is the primary driver of AD pathology, pathological tau accumulation is also associated with dementia in AD patients.Therefore, vaccines targeting both Aβ and Tau simultaneously or sequentially may be required to preventing AD.AADvac1 is an active immunotherapy targeting Tau pathology.This vaccine can generate antibodies targeting conformational epitopes of tau microtubule-binding region, prevent Tau aggregation and pathological spread, and promote Tau clearance to improve AD pathology [43].Davtyan H et al. [44] found that the dual epitope vaccine Aβ/Tau (AV-1953R), or Aβ (AV-1959R) and Tau (AV-1980R) combined with Advax (CpG) can induce a powerful antibody response against various forms of Aβ and Tau pathological molecules.In order to induce a long-term high titer antibody immune response, Liu S et al. [45] used DNA and protein co-immunization to produce high levels of Aβ specific antibody and low levels of IFN-γ, and at the same time induced anti-inflammatory Th2 immune response, thus contributing to the clearance of Aβ and alleviation of AD symptoms.Co-immunization with antigen-matched DNA and protein may be a novel and effective immunotherapy strategy for AD that eliminates Tcell inflammation while maintaining a high level of antibody response.Therefore, active immunization can contribute to the treatment of patients with AD and prevent the pathological development of AD in individuals of presymptomatic stage.

Passive Immunity
Antibodies of anti-Aβ IgM and IgG are present in the serum of every healthy person and may play a role in Aβ homeostasis.Human monoclonal anti-Aβ antibody corresponding to the ubiquitous anti-Aβ antibody is a possible candidate for immunotherapy in AD patients in the future [46].The humanized monoclonal antibody solanezumab is used to increase the clearance of soluble Aβ peptide in the brain [47].Specific forms of Aβ, such as posttranslational modified Aβ peptides, are attractive antibody targets.Hettmann T et al. [48] have generated a new antibody against Pglu3-Aβ, PBD-C06.PBD-C06 is the first to be generated by grafting mouse antigen-binding sequences onto suitable human variable light and heavy chains.PBD-C06 has the same specificity and affinity as mouse precursor antibodies.Elimination of C1q binding does not affect Fcγ receptor binding or phagocytosis in vitro.Therefore, PBD-C06 can enhance the clearance of Aβ and avoid the complement mediated inflammatory response, contribute to reduce the pathology of AD and inhibit neuroinflammation.Excitingly, aducanumab, a human monoclonal antibody targeting Aβ, has been approved for use in Alzheimer's disease.That markers a milestone in immunotherapy for AD [49,50].

Enhance the Phagocytosis of Microglia
Microglia are primary immune cells in the brain, it can sense pathogens and tissue damage, stimulate the production of cytokines, and promote the clearance of Aβ through phagocytosis.Kawanishi S et al. [51] found that bone marrow derived microglia-like cells (BMDML) could effectively phagocytose Aβ in vitro, reducing the number and area of Aβ plaques.The cognitive dysfunction is improved of AD model mice after injecting BMDML cells into the hippocampus.Peripheral blood derived microglia-like cells (PBDML) express microglia markers.PBDML can phagocytose Aβ to reduce the burden of Aβ in the brain, thereby improving cognitive impairment in mice [52].Xu J et al. [53] found that ubiquitin ligase (Peli1) is a key regulator of microglia phagocytosis, and targeting E3 Peli1 can reduce the level of CCAAT/enhancer binding protein (C/EBP) β and CD36 expression, thereby enhancing microglia phagocytosis.Bruton's tyrosine kinase (BTK) is another key regulator of microglia phagocytosis.Inhibition of BTK can reduce the activation of phospholipase γ2 (PLCγ2), and enhance microglia phagocytosis to improve cognitive function in AD patients [54].In vitro and in vivo studies by Park MH et al. [55] showed that N, N'-diacetylp-phenylenediamine (DAPPD) inhibited nod-like receptor protein3 (NLRP3) expression by affecting NF-κB pathway, it has effects of inhibiting neuroinflammation, promoting the phagocytosis of microglia and clearance of Aβ, thereby significantly alleviating the cognitive deficits of AD transgenic mice.
Bexarotene, a vitamin aX receptor (RXRs) agonist, enhanced soluble Aβ clearance in an ApoE-dependent manner in AD mice and improved cognitive, social, olfactory deficits and neural circuit function [56].Liver X receptors (LXRs), as effective inhibitors of inflammatory gene expression, promoted the phagocytosis of microglia in an inflammatory environment.Therefore, LXRs may be an effective target for the treatment of AD [57]. Lee JY et al. [58] found that N-acetylsphingosine (N-AS) increased the secretion of COX2 and SPMs, inhibited of neuroinflammation, increased microglia phagocytosis, and improved memory.In addition, Dedicator of cytokinesis 2 (DOCK2) can regulate innate immunity of microglia and independent of COX2 induction [59].
Dystrophic neurite (DNs) and activated microglia are one of the main neuropathological features of AD.Jović M et al. [60] demonstrated for the first time that shortterm fish oil (FO) supplementation can alter microglia and macrophage behavior in the pre-symptomatic stage of AD, encouraging them to establish a physical barrier around amyloid plaques.This barrier significantly inhibited DNs formation by reducing Aβ content and tau hyperphosphorylation. Omega-3 fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can stimulate microglia to engulf Aβ42.EPA increased the expression level of BDNF, DHA decreased the level of TNF-α, DHA and EPA both decreased the M1 pro-inflammatory markers CD40 and CD86.DHA and EPA are beneficial to AD by reducing proinflammatory cytokine production and inducing phenotypes that reduce M1 microglial activation [61].For MCI patients, omega-3 fatty acid treatment can improve Aβ phagocytosis, improve cognition and daily living activities, and delay the occurrence of dementia [62].
A heptapeptide (XD4) significantly inhibited the cytotoxicity of Aβ, increased microglial phagocytosis of Aβ, reduced Aβ-induced ROS and NO production, improved calcium homeostasis imbalance, and ameliorated memory deficits in AD mice [63].DMXBA, a α7 nicotinic acetylcholine receptor (nAChRs) selective agonist, promotes Aβ phagocytosis and inhibits neuronal γ secretase activity, thereby alleviating brain Aβ burden and cognitive dysfunction [64].Rutin sodium (NaR) promotes metabolic conversion and Aβ clearance from anaerobic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS), improves synaptic plasticity damage, and ultimately reverses spatial learning and memory deficits, which may be related to the provision of sufficient energy (ATP) to remove Aβ from microglia [65].Therefore, regulating metabolism may be a new strategy for the treatment of AD.

Inhibit Microglial Overactivation and Neuroinflammation
Overactivation of microglia can lead to chronic neuroinflammation, and several studies have shown that regulating microglia function and inhibiting neuroinflammation can effectively improve the major pathology related to AD [66,67].TREM2 gene mutations can lead to excessive AKT signaling pathways activated, microglial cells with TREM2 gene express more inflammatory molecules.MK -2206 drugs, which can inhibit AKT, can reverse the inflammation characteristic of microglia, and prevent damage to synapses and neurons in the brain [68,69].The study of Wang Z et al. [70] showed that Lasix could down-regulate the M1 phenotype and up-regulate the M2 phenotype of microglia, inhibit the secretion of pro-inflammatory cytokines TNF-α, IL-6 and NO, down-regulate CD86, COX-2 and iNOS level, and promote expression of anti-inflammatory IL-1 and arginase.It exerts potential therapeutic effect on AD.Furthermore, studies have shown that 1,25D3 can restore dysfunctional innate immune function in AD, balance inflammation, and promote Aβ phagocytosis [71,72].
Chemokines are important regulators of neuroinflammation, and high concentrations of CXCL10 have been found in the brains of AD patients and in animal models of AD.Krauthausen M et al. [73] found that the level of Aβ were significantly reduced in CXCR3-deficient APP/PS1 mice, CXCR3 antagonist could reduce TNF-α secretion and increase the phagocytosis of microglia Aβ.Therefore, CXCR3 may be a therapeutic target for AD.Complement is an inherent component of the immune system and it has been found to modulate disease pathology in mouse models of AD.Phagocytes, including microglia, monocyte and neutrophils, carry C5a receptor.Intermittent treatment of AD mice with oral C5a receptor agonist EP67 enhanced the phagocytic function of phagocytes, reduced amyloid deposition and alleviated neuroinflammation [74].
Reactive microglia are also a pathological feature of AD.Baik SH et al. [75] found that exposure to Aβ induces acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis.Interferon-γ can promote metabolism and reverse microglia glycolytic metabolism and inflammatory function, thereby alleviating AD pathology in 5XFAD mice.Eicosapentaenoic acid (DPAN-6) reduced microglia hyperplasia and inflammation, expression of caspase marker mRNA to alleviating and ameliorating neurodegeneration in mice with advanced AD [76].
Besides astrocyte and microglial responses, the gut microbiome plays an important role in regulating innate immunity and influencing brain function.Minter MR et al. [77] found that long-term changes in intestinal microbial composition and diversity caused by long-term broadspectrum antibiotic therapy reduced the deposition of Aβ plaques, increased soluble Aβ levels, and altered levels of chemokine.And the morphology and response of microglia was significantly changed.In a word, the diversity of intestinal microbial community can regulate the innate immune mechanism of host and affect Aβ amyloidosis.
In conclusion, regulating microglia function and inhibiting neuroinflammation is one of the therapeutic strategies for AD (Fig. 2).

Influence of Traditional Chinese Medicine on Neuroimmune Inflammation
In recent years, some plant components have also been found to play an important role in the treatment of AD.Malva parviflora inhibits neuroinflammation by inhibiting the pro-inflammatory M1 phenotype of microglia and promoting microglia phagocytosis, which is an effective can- didate drug for preventing the progression of AD [78].Xie Z et al. [79] found that Magnolol (MG) can reduce inflammatory response and promote the phagocytosis and degradation of Aβ by peroxisome proliferator activated receptor γ (PPAR-γ).Moussa C et al. [80] showed that resveratrol significantly reduced CSF MMP9, increased the levels of macrophage-derived chemokine (MDC), IL-4 and fibroblast growth factor (FGF-2), regulated neuroinflammation and induced adaptive immunity.Teter B et al. [81,82] showed that low-dose curcumin (Curc-lo) decreased expression of CD33, CD11b, iNOS, COX-2, IL-1β, increased expression of TREM2, stimulating microglial migration to amyloid plaques and phagocytosis.Curcumin is an immunomodulatory treatment, that can mimic anti-Aβ vaccine.It has function of stimulating phagocytes to clear Aβ by reducing CD33 and increasing TREM2 and TyroBP, while restoring the neuroinflammatory networks involved in neurodegenerative diseases.Ginkgolide B (GB) can inhibite NLRP3 inflammatory body activation.In addition, GB enhanced the expression of M2 microglia marker and inhibited the expression of M1 microglia marker, thus preventing the pathological process of AD and weakening neuroinflammatory response [83].Oxymatrine inhibited the overactivation of microglia and regulated M1/M2 polarization of microglia by inhibiting TLR4/NF-κB signaling pathway, and effectively alleviated LPS induced inflammatory response [84].Liquiritigenin also regulates microglia M1/M2 transformation, thereby reducing Aβ levels and reversing memory decline during AD development [85].Cyanidin-3-o-glucoside (C3G) can regulate microglia polarization by activating PPARγ and eliminates Aβ accumulation in AD mice, and it also can upregulate TREM2 to enhance Aβ42 phagocytosis [86].Microglia, dealing with rutin, appeared down-regulate on M1 microglia markers CD86 and iNOS, and up-regulate on M2 microglia markers Arg1 and CD206.Lang GP et al. [87] revealed that rutin can alleviate neuroinflammatory responses by inhibiting TLR4/NF-KB signaling pathway and promoting M1-M2 phenotypic conversion of microglia.
The immune system is closely related to AD.There are a lot of glial cells and inflammatory cytokines in the brain tissue of AD patients.When the glial cells are activated abnormally, it can secrete inflammatory factors, such as IL-1β, IL-6, TNF-α, resulting in neuroinflammatory response.Acupuncture and moxibustion can effectively reduce the central inflammatory response and delay the patho- logical change of AD by regulating the activation of glial cells and the synthesis and release of inflammatory factors in the brain area [88].Electroacupuncture (EA) can improve spatial memory and learning ability in AD mice.EA can improve the symptoms of AD mice by inhibiting M1type polarization of microglia and promoting M2 polarization of microglia.The study of Yang JY et al. [89] showed that EA can alleviate the inflammatory response in the hip-pocampus of mice.Zheng X et al. [90] showed that EA could activate transcription factor EB (TFEB) by inhibiting the Akt-MAPK1-MTORC1 pathway, thereby promoting the autophagy-lysosomal pathway (ALP) in the brain to enhance the cognitive role of AD mice.They also found that EA decreased APP and Aβ loads and inhibited the activation of glial cells in prefrontal cortex and hippocampus of AD mice.Xie L [91] found the same result.In addition, EA affects the immune response by inhibiting the NF-κB pathway and activating the Stat6 pathway.

Summary and Prospect
AD is a typical neurodegeneration disease.Both immunopathogenesis and immunotherapy are frontier research directions in recent years.Immune cells play an important part in the onset and progress of AD.Immune cells have been proved to be involved in neuroinflammation mainly conduct microglia, macrophages, mast cells, T cells and so on.Microglia has been reported to act as macrophages in the brain.In healthy brain, they take the functions of nerve protection by clearing away Aβ and Tau.However, when continuously stimulating by neurotoxic substances, microglia produced chronic irreversible impairment of immunity.It is an effect way to improve the cognitive dysfunction of AD by enhancing the phagocytosis of microglia and macrophages, promoting the transformation of microglia and macrophages from M1 type to M2 type.Furthermore, the activation of mast cells in AD can aggravate neuroinflammation, increase BBB permeability, and then peripheral macrophages and T cells entered the brain.The mechanism mentioned above, to some extent, have demonstrated a role of accelerating the progression of AD.This is also the reason that inhibiting mast cell degranulation, protecting BBB, regulating T cells can alleviate the progression of AD.
Since signs of AD immunity change have been shown in the epidemiological study, the approach of "immunotherapy" and the role of innate immune cells (including microglia and peripheral mononuclear phagocytes) in AD have attracted considerable interest [92].Immunotherapy, anti-Aβ therapy and anti-inflammatory therapy have been proved to have a positive effect on delaying or preventing the progression of AD.Although a lot of researches have been done in this field in recent years (Table 3, Ref. [40][41][42][43]47,49,51,[53][54][55]58,61,64,65,[68][69][70]75,76,[78][79][80][81][83][84][85][86][87][89][90][91][92][93][94]), many important problems still exist.At present few of these drugs are applied to clinical practice, and many researches have only been tested on animals.Whether these treatments will be proved to be beneficial in patients is a pending question.Although some models can well explain the pathological mechanism of AD in vivo, it is still a tricky question to translate laboratory findings into clinical trials.Species differences in metabolism and key molecules expression sequences may bear the brunt of the responsibility.Human pluripotent stem cell (hPSC) technology promises to overcome these limitations to some degree.In addition, positron emission tomography (PET) provides visual evidence of the time course of neuroinflammation and the central pathology of AD in patient and animal disease models [93].With further development in mechanism research and artificial intelligence technology, more breakthroughs will be made in the study of AD immune pathogenesis.Moreover, drugs treating AD will be screened out in a faster and cheaper way.The mechanism of action of drugs will be pointed out and new unexplored therapeutic targets will be revealed, which may provide new methods for the treatment of AD [94].

Fig. 1 .
Fig. 1.The role of immune cells in AD.Under various pathological stimuli (such as Aβ), microglia activation to produce inflammatory factors, which can lead to increased BBB permeability.Macrophages, T cells, mast cells, and neutrophils enter the central nervous system and release inflammatory mediators to further aggravate the inflammatory response.Astrocytes and microglia can interact to induce microglia polarization and impair their phagocytosis.

Fig. 2 .
Fig. 2. Mechanism of action based on microglia in AD treatment Partly.Inhibition of Peli1, BTK, and CXCL3, enhancement of the targets of TREM2 and nAChRs, promotion of mitochondrial OXPHOS, and inhibition of AKT signaling pathway can enhance microglia phagocytosis of Aβ, inhibit inflammatory release, and so improve the pathology and cognition of AD.

Table 2 . Similarities and differences between active and passive immunization.
Similarities Reduces Aβ levels in the central nervous system of patients with Alzheimer's disease Differences Active immunotherapy is designed to induce antibodies to specific amyloid protein (Aβ) with high titers and long-lasting effects Passive input of anti-Aβ antibodies can avoid active immune inflammatory response mediated by harmful T cell activation