Review Article: Microglia in Alzheimer's Disease
Review Article: Microglia in Alzheimer's Disease
Review Article: Microglia in Alzheimer's Disease
Review Article
Microglia in Alzheimer’s Disease
Received 26 February 2014; Revised 28 May 2014; Accepted 3 June 2014; Published 14 August 2014
Copyright © 2014 Ying Li et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Alzheimer’s disease (AD) is a familiar neurodegenerative disease in the elderly. In this paper, we will review current viewpoints
of microglial activation, inflammatory regulatory systems, and their relationship with AD pathology and etiology. Microglia cells
are macrophage and representative of the innate immune system in brain. AD brain is marked by obvious inflammatory features,
in which microglial activation is the driving force. 𝛽-amyloid protein sedimentation activates microglia cells, which causes the
inflammation in AD. Microglia cells have dual roles: they provoke the release of inflammatory factors and cytotoxins leading to
neuronal injuries and death; on the other hand, they have the neuroprotective effects. Through this, we hope to illustrate that the
anti-inflammatory defenses of neurons can be practiced in the future strategy for recuperating the balance between the levels of
inflammatory mediators and immune regulators in AD.
1. Introduction 2. Microglia
Alzheimer’s disease (AD), also called primary Alzheimer’s Glial cells in the brain include astrocyte, oligodendrocyte, and
disease, which lives in the global the third lethal disease, microglia. Oligodendrocyte involves in the formation of the
is a kind of nervous system degenerative disease. Memory, myelin sheath. For neurons in brain cells, astrocytes have a
judgment, thinking ability, sports and mood, feeling reaction, key role for sustaining normal and stable internal environ-
along with the social aging process, have become a serious ment and tissue homeostasis. After brain damage, form and
threat to human life and health. The main mental derange- quantity of astrocyte and microglia change obviously.
ment of this disease is characterized by nerve fibers tangles As a kind of fine cell, microglia (MG) make central ner-
(NFT) in cells, extracellular senile plaques (SP), and a large vous system (CNS) perform an immune activity of scavenger
number of neurons lost. Then, inflammation is one of the sample, which is the vital element of the brain immune
causes of Alzheimer’s disease. AD may be a chronic inflam- surveillance and the exercise of defense function in the brain.
mation of the central nervous system reactions, including In the cells of central nervous system (CNS) they are 5∼
focal brain injury and highly refractory beta-amyloid (A𝛽) 20%. Microglia originated from mesoderm bone marrow
sedimentation; AD inflammation theory was presented. In precursor cells in embryonic period, namely, the mononu-
recent years, the study found that microglia cells (MG) play a clear phagocyte system. In adulthood, microglia in the brain
core role in the pathogenesis of AD, which is currently one of become the innate immune cells, involved in inflammation
the hot topics in the study of the nervous system degenerative and immune response. Kim et al. [1] found that microglia
disease. cells distribution density of the midbrain substantia nigra
2 BioMed Research International
compacta is uneven and significantly higher than other reactive oxygen species (ROS), and so forth [5]. These injured
regions; he also found that the midbrain neurons in the neurons and nerve toxic substances can cause microglia
substantia nigra neurons are more likely to be affected than activation, which trigger a long-standing neurotoxicity cycle
other brain area in neurodegenerative disease, which showed referred as a reactive cycle to microglial cells. Microglia
that the sensitive degree of nerve toxicity of the neurons may activation prompts nerve injury to sustain the development
depend on the distribution density and quantity of microglia. for a long time, leading to reactive microglia cycle, which
Usually, in order to maintain the normal function of nervous will exist permanently. As a result, the damage in neurons is
system, microglia in resting state are characterized by small a long-term chronic process, and it eventually leads to the
cell body and extend to all directions extensions of morpho- development of AD. Microglia neurotransmitter receptors
logical characteristics. One of the most significant features of also express receptors, such as glutamate receptor, GABA
MG is very sensitive to the external environment stimulation, receptors, dopamine receptor; neural hormone receptor,
which is considered to be receptors in pathological cases neuromodulation receptor, histamine receptor, cannabinoid
in CNS [2]. Slight changes of central nervous system will receptor, opioid peptide receptor, chemokine receptors, TNF
cause microglia reaction, and the change of their forms is alpha receptors, interleukin receptors, and so forth; some
generally accepted as a symbol of pathology in the brain.
recognition receptors: toll-like receptor; other receptors:
When the brain tissue lies in the pathological state, MG are
formyl peptide receptor (FPR), calcium receptor, leukotriene
activated from the stationary state into the active state, cells
receptor, notch receptors, and so forth. A lot of slow release of
body swell, synaptic disappearance, and then amoeba-like
these factors may be involved in the substantia nigra striatum
shape formation. Activate their control signals as “on” and
“off ”, the regulation of microglia as [3] “on” signal is a kind of dopaminergic neuron degeneration necrosis of the system.
new molecules, which is very obvious to identifying activated A lot of studies of this view confirm that their application
microglia; “off ” signal is to maintain the signal to hamper of dexamethasone, indomethacin, and minocycline against
microglia, as the default sets; the interrupt signal means the inflammation can protect in the model of AD dopaminergic
alarm sounded. The study found that the role of microglia neurons necrosis [6].
in the development of the AD is a two-way street, that is, On the other hand, microglial can remove the depositing
the immune damage and nerve protective effect, and the A beta by phagocytosis cells and express on the gene of
excessive activation can cause or aggravate neuron damage. antioxidant, in addition, and can secrete neurotrophic factor
Microglia participate in a variety of nervous system degener- of nerve protection. Activated microglia can quickly increase
ative diseases and the occurrence and development of the dis- the expression of major histocompatibility complex and then
eases’ process. In recent years, studies have shown that exces- turn into antigen presenting cells and have stronger phagocy-
sive microglial cells activation often occurred in a chronic tosis. Microglia express the antioxygens of heme oxygenase-1
condition, which produces a large number of cytokines and (HO-1) and nuclear factor erythroid-related factor 2 (Nrf 2),
ROS production. The abnormal activation of microglia and which play a critical role in cell survival [7].
the induced inflammation are a common link of the process
which is caused by dopaminergic neuron damage.
Looking from the ultrastructure, microglia into phago- 3. MG in Inflammatory Injury
cytes can remove necrotic neurons and then protect the
integrity of the necrotic neurons surviving around them. There are many evidences that nerve cells apoptosis is
From the point of views of function, microglia can be acti- closely related to the activation of MG; A beta activate MG,
vated by releasing oxygen free radical, nitric oxide, protease, which mediate immune inflammatory reaction and cause the
and inflammatory cytokines and take the cytotoxic effect. occurrence of AD which is characteristic of cells apoptosis
At the same time it also can secrete nerve growth factor for and the cognitive decline [8]. Long-term activation of MG
supporting tissue repair [4]. Many signal molecules including through the secretion of active cytokines and molecules can
many cytokines in the central nervous system of normal increase the formation of age spots and the contents of the
brain development process play an important role in neural tau protein hyperphosphorylation, which promote the nerve
immune regulation, which also participate in the neural tangles [9]. The study indicated that N end of A beta is a
pathological immune reaction in neurodegenerative diseases. necessary structure of MG to cohere; it can capture MG to
These related molecules in cell surface or internal can be age spots, and C terminal of A beta is induced by MG, which
used as a marker of microglia and differ from the other plays the role of toxic peptides. MG surface can combine with
cells in the central nervous system, such as ILB4, CD11b, A beta receptors, such as scavenger receptors and advanced
and so forth. Aging and the brain A beta deposition are glycosylated end products receptor. Combined with A beta,
considered to be the major risk factors for the nerve degen- microglia can be activated and produce toxic products such
eration of AD and associated with the activation of microglia as free radical, cytokine, and glutamate agonists, which will
(Figure 1). A beta activate microglial cells to produce a variety accelerate neuronal death [10]. Activated MG can secrete
of inflammatory factors and make neurotoxic effect, cell and release TNF-alpha, IL-1, IL-6, CD40, colony stimulating
inflammatory molecules which include tumor necrosis factor factor, ring oxidase 2, prostaglandin (PG), and some chemical
(TNF alpha), interleukin 1 beta (IL-1 beta), interleukin 6 (IL- chemokines. These generated cytokines in turn affect the
6), chemokine macrophage inflammatory protein-1 (MIP-1), glial cells and neurons to promote the production of other
monocyte chemotactic protein 1 (MCP-1), complement and inflammatory molecules for forming a positive feedback
BioMed Research International 3
A beta fiber
Neuron
IL-6 NADPH oxidase
TNF
CD40
NO C5a Respiratory burst
Rac GDP
GDP Rac
p67phox gp91/p22phox Oxidative damage
GTP Rho GDI
Actin rearranging
Phagocytosis
Microglia
A beta chips
Figure 1: A beta activates inflammatory mediators and the complement system on microglia and then generates free radicals and makes toxic
effects on neurons; on the other hand glial cells phagocytize A beta chips.
loop in the body; then inflammatory factors increase, and IL-6 can further promote the neuron to degenerate in the
eventually lead to neuronal degeneration necrosis [11]. acute phase reaction. Therefore, IL-6 plays a key role in the
development of AD.
3.1. IL-1𝛽. It is generally believed that A beta stimulate mi-
croglia to produce IL-1 beta, which can prompt the synthesis 3.3. TNF-𝛼. TNF alpha is the one of the cytokines which
of APP and A beta deposition. IL-1 beta can increase the con- are secreted by the activated MG; it plays a central role
centration of Ca2+ in neurons and cause neuron dysfunction in inflammatory cytokine network; its toxic effects may
or death. Halle et al. [12] showed that as a cytoplasm receptor, induce expression and secretion of a variety of the related
NALP3 inflammatory body is involved in regulating the inflammation factors through activating the cell apoptosis;
activation and secretion of IL-1 beta. After being swallowed by it can strengthen the N-methyl-D-aspartate (N-methyl-D-
microglia, A beta fibers activate NALP3 inflammatory body, aspartate, NMDA) receptor and mediate the neural toxicity
and caspase 1, eventually, produces and releases proinflam- and increase the glutamate which may injury the nerve cells
matory cytokines IL-1 beta. A beta can activate IL-6 and IL- [16]; it can also induce the colony stimulating factor (CSF)
1; TNF alpha then releases cytokines, such as complement, and further enlarge the inflammation reaction. In addition,
chemokines, and adhesion molecules induced production it can affect the neuron membrane potential and lead to the
increasing. These immune inflammatory factors, on the disorder of intracellular Ca2+ balance for a long range, which
contrary, activate microglia, form a positive feedback loop are associated with the abnormal cell function in the process
in the body and produce inflammation cascade amplification of inflammation [17, 18].
effect, eventually lead to neuronal degeneration necrosis and
inflammation and neurons injury in the brain [13]. 3.4. CD40. CD40 is a member of the TNF alpha receptor
superfamily; it was found on the surface of the antigen cell like
3.2. IL-6. IL-6 is a kind of pleiotropic cytokine, it is mainly B lymphocytes, dendritic cells, and activated macrophages;
produced by the lymphocytes, fibroblasts, endothelial cells, its natural ligands CD40 L and CD154 express on the surface
neurons, and glial cells, which are activated by inflammation of the activated T cells [19]. The role of CD40 molecules in
or other factors. IL-6 can prompt cute proteins to deposit the proinflammatory response caused by MG has aroused
in the neuritis spot and adjust the synthesis of APP. The the attention of many scholars, since it was found that
compounds of IL-6 and sIL-r can enhance the transcription CD40 interacts with its related ligand CD154, which leads to
and expression of APP [14, 15]. Studies had found that IL-6 secrete cytokines and neurotoxic substances. Cytokines, such
in the transgenic mouse can promote the reactive glial cell as interferon gamma (IFN-gamma), induce the abnormal
hyperplasia. At the same time, IL-1 alpha/beta, TNF alpha, expression of microglia by TNF alpha and facilitate the CNS
intercellular adhesion molecule 1 (ICAM 1), and acute phase neural immune cascade reaction [20]. Therefore, inhibiting
response proteins EB 22/5, 3 genes also raised obviously; the expression of CD40 can relieve the inflammatory reaction
4 BioMed Research International
and nerve damage; eventually will be good for the treatment But if it is released excessively, it will damage the membrane
of nerve inflammatory diseases in the CNS. structure, protein and DNA through various channels and
lead to neuronal necrosis or apoptosis [24], which eventually
3.5. Complement. Study found that A beta can activate the damage the nervous system. Nitric oxide synthase (NOS)
classic and bypass complement way; after activating the is the unique enzyme for generating endogenous NO; it
complements C3a, C4a, and C5a are produced; these small is mainly expressed by iNOS in pathological situation. Its
fragments have the characteristic of the inflammatory stimuli. expression is not only one of the symbols of reactive glial cell
C5a combines with the receptors on the membrane of MG proliferation but also related to neuronal damage. INOS can
and then causes a strong breathing outbreak and produces continuously and catalytically catalyze to produce NO; exces-
a large amounts of toxic superoxide free radicals and makes sive amount of NO has the potential neurotoxicity, which
neurons damage [21]. In addition that the complement can is an effective source of oxidative stress in the pathological
release an amount of the inflammatory factors and cause the process of AD.
inflammatory reaction in the brain, it can activate MG. The
inflammatory reaction can promote A beta to deposit and 4.3. Drd2. Dopamine receptor is a vital member of the
aggravate to form nerve plaques and then result in a vicious dopamine signal system of the neurotransmitter in the brain
cycle, eventually develop AD [21]. and plays a key role, including emotion, the neural activity of
Overall, the beneficial roles of cytokines which are pro- addiction, voluntary movement, and many other advanced
duced by activated MG are very limited; the main effect is to functions. The studies suggest that dopamine D2 receptor
amplify the inflammatory process and the cytotoxic effect in (Drd2) is also expressed in microglial cells [25] and can affect
the different stages of AD, eventually, leading to a selective the activation of CD4+ T lymphocyte; 18 elderly people’s aver-
brain regions degeneration and cholinergic neuron death age level of Drd2 declined obviously [26, 27], which indicated
through the chronic and local inflammation. that Drd2 may participate in the regulation of innate immu-
nity of the central nervous system. In 2009, in the United
4. The Damage of Inflammatory Medium States, Dr. Glass said that, in the inflammatory response
process induced by bacterial endotoxin LPS, microglial
4.1. ROS. ROS is a kind of vivid oxygen free radicals which cells were first activated, and then astrocytes accepted the
are produced in the aerobic metabolism process of cells immune signal of microglia and were passively activated; in
and the material which can be converted into free radicals, both, mutual cooperation ultimately promoted the neuronal
mainly includes hydroxyl free radical (OH) and superoxide damage and degradation [28] (Figure 2). There is a kind of
anion (O2 2− ) and hydrogen peroxide (H2 O2 ), and so forth. Cryab protein expressed in astrocytes; Cryab protein is a
ROS in the low-medium concentration play an important kind of small molecular heat shock protein, which plays the
physiological role in body; they participate in the process role of inhibiting inflammation and neuroprotection [29].
of the body’s immune and resist the damage to body such In the condition of outside harmful stimulations, due to
as exogenous bacteria and microbes. They also can be the inhibitory effect of proinflammatory factor expression of
used as the second messenger to regulate and control the Cryab, inflammation can be controlled within a certain range
gene expression and the signal transduction pathway and when the Drd2 signaling pathways of microglia to astrocytes
participate in the cell growth, differentiation, and many other are weakened; Cryab expression level is reduced when the
functions. In the condition of inflammation or trauma, too outside world harmful stimulus arrives, microglia could not
much ROS are produced and induce the cell injury and effectively cope with and lose effective restriction for the
apoptosis, which is due to the excessive accumulation of the inflammatory response and then involve in the neuronal
oxidation product of lipid, carbohydrate, protein and DNA, degeneration and aging process.
and the antioxidant system defect. ROS can be generated
through various channels, but their main way is catalyzed
by NADPH oxidase [22]. The NADPH oxidase is the main 5. MG’s Theory of Beta-Amyloid
enzyme body, which is the origin of AD oxidative stress A𝛽, which is generated by the APP, plays a key role in AD.
and is involved in the occurrence and development of AD A𝛽 itself perhaps has no neurotoxicity; it does not cause
process. The compounds of NADPH oxidase are stationary obvious neurologic symptoms, until the inflammatory factors
under normal circumstances; A beta deposition can make the and A beta synergistically affect microglia and induce A beta
NADPH enzyme activation. Studies have found that in AD obvious toxic effects on neuron [30]. The formation of senile
the NADPH oxidase activity increased [23]. It indicated that plaques is due to the abnormal sedimentary of A𝛽, that is,
it played a potential role to prompt the activation of NADPH the typical pathologic characteristics of the AD. A𝛽1−40 and
oxidase of microglia in AD development. A𝛽1−42 are the most common subtypes of A𝛽, which is the
main component of senile plaques. They are two kinds of
4.2. NO. NO is an important endogenous medium of vascu- forms; one is the higher aggregation degree A beta [5]; the
lar activity and immune characteristics. In the central ner- other one is a kind of smaller molecular weight of the soluble-
vous system, as a special neurotransmitter NO is involved in A beta oligomers [31]. White [8] thinks that two forms of A
synaptic plasticity and neuronal growth, learning and mem- beta have important roles in the development process of AD.
ory and behavior, and many other physiological mechanisms. Oligomers play a main role in the early stages of the disease,
BioMed Research International 5
Normal Pathogenic factor can change the activity of related kinase which caused
LPS LPS the tau phosphorylation [38]. Sy et al. [39] found in AD
Stress transgenic mouse, the change of tau protein from soluble to
Resting microglia
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Conflict of Interests protein transcription and expression by the soluble interleukin-
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