1. Introduction
Alzheimer’s disease (AD), which is the most common type of dementia, is
characterized by senile plaques formed by abnormal aggregation of A 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,
A, 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), CD14T
and CD34T cells [5]. Therefore, a well-functioned immune response and
endocytosis 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 neuro-immune inflammation. Based on the above content, we aim to
inspire new ideas for AD treatment.
Fig. 1.
The role of immune cells in AD. Under various pathological
stimuli (such as A), 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.
2. The Role of Immune Cells in AD
2.1 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
pro-inflammatory function through secreting pro-inflammatory factors. Under the
induction of lipopolysaccharide (LPS) and interferon (IFN-),
M1 release a large amount of NO, tumor necrosis factor
(TNF-), interleukin-1 (IL-1), 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 (TGF-), IL-4, IL-10 and vascular endothelial growth
factor (VEGF). M2 plays an anti-inflammatory role by blocking NO production,
inhibiting nuclear factor B (NF-B) 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-1/CXCR4-mediated chemotaxis, and ultimately leads to impaired response to
A 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 A
uptake by ESC-derived microglia (hMGL) in vitro in an ApoE-dependent
manner and attenuate A 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 microglia-mediated 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 pro-inflammatory mediators IL-1, P40, inducible
nitric oxide synthase (iNOS), CCL-3, CCL-4 and CXCL-1 were higher in AD model.
2.2 Monocytes/Macrophages
In AD, A 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 A
phagocytosis and inflammation in macrophages. THP-1 macrophages’ SHARPIN
expression stimulated by A can promote A phagocytosis and the
expression of pro-inflammatory markers. In addition, A-stimulated
SHARPIN promotes the death of differentiated SHSY5Y neurons. In THP-1
macrophages, there was a closely positive correlation between plasma A42
level in mild cognitive impairment patients and SHARPIN expression in peripheral
blood monocytes of AD [22]. In addition, the presence of ApoE4 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
A1-42, which decline with age, and reduce the expression of Toll-like
receptor 2 (TLR2) associated with A 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.
2.3 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 A 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
CD47/1 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].
2.4 T Cells
The clearance of A 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 CD8T cells in AD, and
the level of activated CD8T 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 A 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 CD8T cell
reactivity was increased in AD, but also reactive memory T cells were produced
[31].
2.5 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 A 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, 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].
2.6 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-B hyperactivation and C3 elevation in
astrocytes aggravate A pathology and neuroinflammation in AD mice, while
C3aR antagonist (C3aRA) ameliorate plaque burden and microglia hyperplasia.
A activates NF-B 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 A phagocytosis [36]. The correlation between
astrocytes and microglia may provide new insight for targeted therapy of AD.
The roles of various immune cells in AD are summarized in Table 1 (Ref. [7, 8, 10, 11, 13, 14, 16, 17, 18, 20, 21, 23, 26, 29, 30, 31, 33, 34, 35, 36]).
Table 1.The role of various immune cells in AD.
Immune cell type |
Effect in AD |
Microglia |
M1 microglia secretes NO, TNF-, IL-1, IL-6, superoxide and so on [7, 8]. C3R, CD14 and CD36 are upregulated [18, 20]. Leading to an inflammatory reaction and damages neurons. |
The phagocytic function of microglia are impaired and A deposition was increased because of TREM2 expressed defective [10, 11, 13, 14] and APOE4 genotype [16, 17]. |
Monocytes/macrophages |
Phagocytic A, has protective effect; stimulate oxidative stress, has damage effect [21, 23]. |
Mast cells |
After mast cell activation, rapid degranulation via CD47/1 integrin membrane complex releases inflammatory mediators to aggravate AD neuroinflammation [26]. |
T cells |
CD4 and CD8T cells increased reactivity, the brain protective immune response to A monitoring disorders, increased A accumulation [29, 30, 31]. |
Neutrophils |
Neutrophils release inflammatory mediators (such as MIF, IL2, and MPO) that promote the progression of AD neuroinflammation [33, 34]. |
Astrocytes |
A activates astrocyte NF-κB, leading to the release of complement C3. Astrocyte and microglia can interact to induce microglia polarization and aggravate A pathology and neuroinflammation [35, 36]. |
3. Treatment of AD Based on Neuroimmune Inflammatory Mechanism
3.1 Immunotherapy
Autoimmune characteristics are associated with AD. Autoantibodies against
receptor for advanced glycation end products (RAGE) and cytotoxic A42
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 4 and IRF7A
alleles) may affect the brain immune efficiency [38]. Gericke C et al.
[39] have found that A deposition is accompanied by a marked reduction
in MHC II levels on brain antigen-presenting cells (APCs). Furthermore,
A 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 A and tau in AD.
AD patients show severe cognitive deficits accompanied by increased brain
aggregation deposits of A. Modulation of A homeostasis has been
suggested as a therapeutic approach for AD patients. It has been shown that
active and passive immunization with A (Table 2) can restore different
forms of A balance in the brain, leading to improvement of cognitive
function in mouse models of AD.
Table 2.Similarities and differences between active and passive
immunization.
|
Active immunity and AD |
Passive immunity and AD |
Similarities |
Reduces A levels in the central nervous system of patients with Alzheimer’s disease |
Differences |
Active immunotherapy is designed to induce antibodies to specific amyloid protein (A) with high titers and long-lasting effects |
Passive input of anti-A antibodies can avoid active immune inflammatory response mediated by harmful T cell activation |
3.1.1 Active Immunity
Active immunotherapy targeting A is the most promising strategy for the
prevention or treatment of AD. Active immunotherapy is designed to induce
specific A antibodies, which can reduce the level of A in the
central nervous system of AD patients. AN-1792, the first clinical trial based on
a full-length A42 vaccine, showed that a safe and effective AD vaccine
should induce high titers of anti-A 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-A antibodies, and reduced AD like lesions in the mouse brain and
simultaneously didn’t induce microglial activation. In addition, antibodies which
anti-A and anti-influenza have a strong therapeutic effect by using
chimeric viruses synthesized from two influenza viruses as routine inactivated
vaccines [42].
Although A is the primary driver of AD pathology, pathological tau
accumulation is also associated with dementia in AD patients. Therefore, vaccines
targeting both A 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 A/Tau (AV-1953R), or A
(AV-1959R) and Tau (AV-1980R) combined with Advax (CpG) can induce a powerful
antibody response against various forms of A 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 A specific antibody and low levels of IFN-, and at
the same time induced anti-inflammatory Th2 immune response, thus contributing to
the clearance of A 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 T-cell 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 pre-symptomatic stage.
3.1.2 Passive Immunity
Antibodies of anti-A IgM and IgG are present in the serum of every
healthy person and may play a role in A homeostasis. Human monoclonal
anti-A antibody corresponding to the ubiquitous anti-A 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 A peptide in the brain [47]. Specific forms of A, such
as post-translational modified A peptides, are attractive antibody
targets. Hettmann T et al. [48] have generated a new antibody against
Pglu3-A, 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 Fc receptor binding or
phagocytosis in vitro. Therefore, PBD-C06 can enhance the clearance of
A and avoid the complement mediated inflammatory response, contribute to
reduce the pathology of AD and inhibit neuroinflammation. Excitingly, aducanumab,
a human monoclonal antibody targeting A, has been approved for use in
Alzheimer’s disease. That markers a milestone in immunotherapy for AD [49, 50].
3.2 Regulate Microglia Function and Inhibit Neuroinflammation
3.2.1 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 A through phagocytosis. Kawanishi S et al. [51] found that
bone marrow derived microglia-like cells (BMDML) could effectively phagocytose
Ain vitro, reducing the number and area of A 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 A to reduce the burden
of A 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) 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 2 (PLC2), 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’-diacetyl-p-phenylenediamine (DAPPD) inhibited nod-like receptor protein3
(NLRP3) expression by affecting NF-B pathway, it has effects of
inhibiting neuroinflammation, promoting the phagocytosis of microglia and
clearance of A, thereby significantly alleviating the cognitive deficits
of AD transgenic mice.
Bexarotene, a vitamin aX receptor (RXRs) agonist, enhanced soluble A
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 short-term 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 A content and tau
hyperphosphorylation. Omega-3 fatty acids (FAs) such as docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA) can stimulate microglia to engulf
A42. EPA increased the expression level of BDNF, DHA decreased the level
of TNF-, 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 A
phagocytosis, improve cognition and daily living activities, and delay the
occurrence of dementia [62].
A heptapeptide (XD4) significantly inhibited the cytotoxicity of A,
increased microglial phagocytosis of A, reduced A-induced ROS
and NO production, improved calcium homeostasis imbalance, and ameliorated memory
deficits in AD mice [63]. DMXBA, a 7 nicotinic acetylcholine receptor
(nAChRs) selective agonist, promotes A phagocytosis and inhibits
neuronal secretase activity, thereby alleviating brain A
burden and cognitive dysfunction [64]. Rutin sodium (NaR) promotes metabolic
conversion and A 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 A from microglia
[65]. Therefore, regulating metabolism may be a new strategy for the treatment of
AD.
3.2.2 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-, 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 A 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
A were significantly reduced in CXCR3-deficient APP/PS1 mice, CXCR3
antagonist could reduce TNF- secretion and increase the phagocytosis of
microglia A. 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 A induces acute microglial inflammation
accompanied by metabolic reprogramming from oxidative phosphorylation to
glycolysis. Interferon- 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 broad-spectrum antibiotic
therapy reduced the deposition of A plaques, increased soluble
A 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 A amyloidosis.
In conclusion, regulating microglia function and inhibiting neuroinflammation is
one of the therapeutic strategies for AD (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 A, inhibit inflammatory
release, and so improve the pathology and cognition of AD.
3.3 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 candidate 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 Aby peroxisome proliferator activated receptor (PPAR-).
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-1,
increased expression of TREM2, stimulating microglial migration to amyloid
plaques and phagocytosis. Curcumin is an immunomodulatory treatment, that can
mimic anti-A vaccine. It has function of stimulating phagocytes to clear
A 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-B signaling pathway, and effectively alleviated LPS induced
inflammatory response [84]. Liquiritigenin also regulates microglia M1/M2
transformation, thereby reducing A levels and reversing memory decline
during AD development [85]. Cyanidin-3-o-glucoside (C3G) can regulate microglia
polarization by activating PPAR and eliminates A accumulation
in AD mice, and it also can upregulate TREM2 to enhance A42 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-1, IL-6, TNF-, resulting in neuroinflammatory response.
Acupuncture and moxibustion can effectively reduce the central inflammatory
response and delay the pathological 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 M1-type
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 hippocampus 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
A 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-B pathway and
activating the Stat6 pathway.
4. 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 A 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-A 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].
Table 3.Summary of treatment of AD based on neuroimmune inflammatory
mechanisms.
Model |
Drug |
Mechanism of action |
Reference |
Clinic trial |
AN-1792 |
Expression of anti-A antibody |
2014 [40] |
Clinic trial |
Lu AF20513 |
Expression of anti-A antibody |
2013 [41] |
AD mice |
Flu-Abeta1-7 or flu-Abeta1-10 |
Expression of anti-A antibody |
2011 [42] |
Clinic trial |
AADvac1 |
Tau antibodies are produced |
2019 [43] |
Clinic trial |
Solanezumab |
To remove A |
2018 [47] |
Clinic trial |
Aducanumab |
To remove A |
2021 [49] |
AD mice |
A beta/Tau (AV - 1953 - r) |
Expression of anti-A and anti-Tau antibodies |
2016 [92] |
AD mice |
PBD-C06 |
Inhibits A and inflammation |
2020 [93] |
AD mice |
BMDML cells were injected |
Inhibition of A |
2018 [51] |
AD mice |
Targeted E3 Peli1 |
Microglia phagocytosis was enhanced |
2020 [53] |
AD mice |
Inhibition of BTK |
Microglia phagocytosis was enhanced |
2019 [54] |
AD mice |
DAPPD |
Microglia phagocytosis was enhanced |
2019 [55] |
AD mice |
N-acetylsphingosine |
Microglia phagocytosis was enhanced |
2020 [58] |
Human CHME3 microglial cells |
DHA and EPA |
Decreased M1 microglia activation |
2013 [61] |
AD mice |
DMXBA |
Microglia phagocytosis was enhanced |
2018 [64] |
AD mice |
NaR |
Enhanced clearance of A |
2019 [65] |
AD mice |
MK-2206 |
Inhibit microglia activation |
2021 [68, 69] |
Microglial cells |
furosemide |
The phenotype of pro-inflammatory microglia M1 was down-regulated and that of anti-inflammatory microglia M2 was up-regulated |
2020 [70] |
AD mice |
EP67 |
Microglia phagocytosis was enhanced |
2019 [94] |
AD mice |
Recombinant interferon - |
Inhibition of inflammation |
2019 [75] |
AD mice |
DPAn-6 |
Inhibition of inflammation |
2020 [76] |
AD mice |
Malva parviflora |
Inhibit the pro-inflammatory M1 phenotype of microglia |
2019 [78] |
Transgenic C. elegans |
Magnolol |
Inhibition of inflammation |
2020 [79] |
Clinic trial |
Resveratrol |
Inhibition of inflammation |
2017 [80] |
AD mice |
Curcumin |
Inhibit the pro-inflammatory M1 phenotype of microglia and promote phagocytosis |
2019 [81] |
BV2 cells |
Ginkgolide B |
Inhibition of inflammation |
2021 [83] |
N9 microglia cells |
Oxymatrine |
Inhibition of inflammation |
2021 [84] |
AD mice |
Liquiritigenin |
The phenotype of pro-inflammatory microglia M1 was down-regulated and that of anti-inflammatory microglia M2 was up-regulated |
2021 [85] |
AD mice |
Cyanidin-3-O-glucoside |
Microglia phagocytosis was enhanced |
2022 [86] |
BV2 cells |
Rutin |
The phenotype of pro-inflammatory microglia M1 was down-regulated and that of anti-inflammatory microglia M2 was up-regulated |
2021 [87] |
AD mice |
EA |
The phenotype of pro-inflammatory microglia M1 was down-regulated and that of anti-inflammatory microglia M2 was up-regulated |
2021 [89] |
AD mice |
EA |
Microglia phagocytosis was enhanced |
2021 [90] |
AD mice |
EA |
Inhibit microglial overactivation |
2021 [91] |
Author Contributions
HC, CD and ZM contributed equally to this work. SM provided guidance for the topic selection and revision of the manuscript. All authors read and approved
the final manuscript.
Ethics Approval and Consent to Participate
Not applicable.
Acknowledgment
Not applicable.
Funding
This work was supported by Project of COVID-19 Emergency Response Project of Shanghai
Sixth People’s Hospital in 2022(ynxg202218), Three-year Action Plan (2021-2023) of
Shanghai Municipality for Further Accelerating the Inheritance, Innovation and
Development of Traditional Chinese Medicine [ZY(2021-2023)-0205-04], Construction
of East China Area and Municipal TCM Specialist Disease Alliance [ZY(2021-2023)-0302], Provincial General Project of Innovation and Entrepreneurship training Program for
College students in Heilongjiang Province (S202210228075)
Conflict of Interest
The authors declare no conflict of interest.
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