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Editor—Summer Leaf
of the CNS.
In the pathogenesis and disease progression of Alzheimer's disease (AD), this cross-dialogue between cells can amplify its function
through mutual crosstalk.
Therefore, when one of the cells has pathological changes, it often directly or indirectly affects other cells, and microglia play a leading role
in this process.
By elucidating existing drugs and therapeutics, targeting microglia and dialogue with other cells at different time windows may help alleviate neuroinflammation caused by AD, reduce neuronal death and provide an appropriate microenvironment
for nerve regeneration according to the characteristics of microglial continuity.
This may provide new ideas
for the treatment of neuroinflammatory degenerative diseases such as AD, which are currently progressing slowly.
Previous studies have used the two ends of microglia polarization as the basis for distinguishing the M1 pro-inflammatory/M2 anti-inflammatory paradigm, but this dichotomy is too simple to fully describe the dynamic change process
of microglial polarization.
Through literature research, it is found that distinguishing metabolic pathways such as microglia surface markers, cellular glucose metabolism, and cell epigenetic markers helps us understand the characteristics of
microglial continuity changes in different time windows in AD state.
Microglia usually accumulate around amyloid plaques and Tau protein due to their characteristic chemotaxis, and microglia have extensive dialogue and crosstalk
with other cells under normal physiological or AD pathological conditions.
This suggests that microglia play a key role in neuroinflammatory diseases such as AD, and by exploring the mechanism of interaction between microglia and other cells, it will provide a theoretical basis for reducing neuroinflammation and delaying neuroinflammatory degenerative diseases such as AD.
October 10, 2022, Ma Stub, Shanxi University of Traditional Chinese Medicine Based on the research results of his team and other teams in recent years, the professor's research group published a paper entitled "Neural Regeneration Research" Review article "The effects and potential of microglial polarization and crosstalk with other cells of the central nervous system in the treatment of Alzheimer's disease"
。 Master students Yige Wu and Associate Professor Lijuan Song are the co-first authors of the paper, and Professor Ma Xinggen is the corresponding author
.
The microglia phenotype in AD was analyzed to be characterized by continuous changes and extensive dialogue
with other CNS innate cells and peripherally invading immune cells.
Patients with the disease may benefit
from targeting microglial phenotypic changes and dialogue with other cells.
(Read more: The latest progress of the Ma stub team, see Logic Neuroscience report: Front Cell Neurosci.
) - Using bibliometrics to analyze the research trends of astrocytes and stroke; Neural Regen Res Review—Advantages of Rho kinase and its inhibitor Fasduil in the treatment of neurodegenerative diseases; A Review of Front Aging Neurosci – The double-edged role of astrocytes in neurovascular units after cerebral ischemia)
Microglia are disease regulators in AD
AD is a degenerative disease of CNS, with cognitive function and behavioral disorders as the main clinical features, and has received increasing attention in modern society [1].
As innate immune cells of the CNS, microglia can participate in the occurrence and progression of neurodegeneration by activating inflammatory signaling pathways, thereby affecting the prognosis of AD patients [2].
Based on specific characteristics, activated microglia can be divided into two broad categories: M1 and M2 [3-9].
This simplified dichotomy is still used in clinical and experimental research
.
However, as far as current research progress is concerned[10-12], microglia in AD are known to exist in a number of different activation states, and the continuity of microglial polarization can be demonstrated by describing their continuity changes (Figure 1).
。 Currently, polarization of pro-inflammatory M1 microglia is generally thought to be associated with chronic neuroinflammation in AD, with the deposition of β-amyloid (Aβ) follows CNS inflammation levels increase [13].
Even the many factors produced by M2 type microglia, which are thought to have anti-inflammatory functions, are not entirely beneficial to AD [14].
Therefore, in order to treat AD, it is necessary to adjust the delicate therapeutic balance
by altering the polarization of microglia at different stages of AD.
Figure 1 The continuous process of microglial polarization (Source: Wu Y, et al.
, Neural Regen Res, 2022).
Migration and phagocytosis of AD microglia
Microglia, as the main immune cells responsible for maintaining homeostasis within the CNS, continuously monitor for signs of neurological damage (such as pathogen invasion or tissue damage) and then generate a cascade of responses to address damaging factors encountered in immune defenses [15.
16]
。 During the pathogenesis of AD, microglia are constantly activated and subsequently become round migrating cells called "amoeba" cells [17,18].
These activated microglia exhibit migration and phagocytosis capabilities, encapsulating Aβ and degrading other substances [19], which in turn affects the prognosis
of AD.
(1) Migration of microglia in AD
The formation of amyloid plaques and tau protein tangles in the brain is a typical pathological feature of AD, and microglia usually gather around them due to the ability of amyloid plaques and tau proteins in AD patients to migrate [20]。 One of the main processes by which microglia transition from a quiescent to an activated state is migration and aggregation [21].
However, the specific mechanism behind the migration remains unknown
.
The migration effect of microglia is related to the release of multiple cytokines and the activation of many signaling pathways [22].
Microglia reside in the CNS in a physiological state and are called resting microglia
.
They have the characteristics of small cytoplasms, elongated protrusions and more branches on the surface, and are the gatekeepers of the CNS [23].
Microglia are constantly moving, can sense changes in the surrounding environment, and maintain the body's homeostasis
.
However, microglia in pathological states such as AD are activated by a variety of factors and surface-related receptors, such as TREM2 and toll-like receptors (TLRs), which can be associated with Aβ and apolipoprotein E (ApoE) bind to each other and migrate to the site of injury [24,25].
(2) Phagocytosis of microglia in AD
During the pathogenesis of AD, Aβ deposition in the brain is often accompanied by glial cell proliferation and lipid deposition, which leads to a continuous progression of the inflammatory response [26].In addition, microglia can recognize amyloid through receptors such as TREM2, TLRs, and CR1, creating a unique signaling cascade
.
This process drives microglia recognition and migration to the lesion site [27].
Subsequently, microglia begin to engulf age age spots (SPs) and other pathogenic products by phagocytosis and microphagocytosis [28,29].
Phagocytosis allows soluble Aβ and tau proteins to be absorbed into microglia, and upon binding to intracellular substances and fusion with endosomes and lysosomes, vesicles and their contents are destroyed by acid hydrolases and tissue hydrolases in lysosomes, anti-inflammatory mediators are released, and lipid clearance is improved[30]
。
Microglia can directly engulf AD toxic products such as Aβ and tau proteins, which have advantages
in AD therapy.
However, recent studies have shown that microglia phagocytosis is not always beneficial, in part related to specific clinical stages [31].
In patients with only pathophysiological changes in AD but no or only mild clinical symptoms, enhanced microglial phagocytosis reduces Aβ levels, slows the formation of SP, and prevents the production of nerve fiber tangles (NFTs), These help prevent the onset of AD and delay the clinical progression of AD [32].
Due to the absence of lysosomes, the phagocytic capacity of microglia decreases after phagocytosis of Aβ and tau proteins [33].
What's more, after exerting phagocytosis, the cell metabolism produces a cascade of inflammatory vesicles (such as NLRP3) and inflammatory cytokines (such as TNF-α, IL-1) The presence of microglia in turn causes microglia to polarize in the pro-inflammatory direction, thereby inducing the secretion of pro-inflammatory cytokines, exacerbating the inflammatory response, reducing the phagocytosis of Aβ, and promoting the pathological response to tau protein [34].
At the same time, microglia's phagocytic capacity decreases with age or prolonged exposure to increased Aβ load [35].
Crosstalk between microglia and other cells in AD
Different types of glial cells in the CNS, including microglia, astrocytes, and oligodendrocytes, perform different functions and coordinate the homeostasis of the CNS and neurons through a variety of intercellular crosstalk mechanisms known as neuroimmunity [36].
Cells have the ability to amplify their function by crosstalk with each other [37].
Therefore, when diseases affect one of these cells, they usually directly or indirectly affect the other cells (Figure 2).
Figure 2 Crosstalk between microglia and other cells in Alzheimer's disease
(Source: Wu Y, et al.
, Neural Regen Res, 2022).
(1) Crosstalk between microglia and astrocytes in AD
Activation and polarization of microglia and astrocytes are often thought to exacerbate AD development and aging.
Although the underlying cellular and molecular mechanisms are unknown, multiple cytokines and signaling pathways are known to be involved in the activation
of microglia and astrocytes in AD.
In addition, activation and polarization of microglia often contribute to astrocyte activation, leading to neuronal toxicity and aggravating the inflammatory environment [38].
Similarly, due to astrocyte activation, more microglia transition from quiescent to activated
.
In AD, there is extensive dialogue and crosstalk between these two types of glial cells [39].
Polarized microglia communicate with astrocytes through inflammatory crosstalk and other mechanisms, activating and polarizing astrocytes [40].
Pathological products of AD (such as Aβ and tau) contribute to microglial polarization, predominate the pro-inflammatory phenotype of microglia, and induce pro-inflammatory factors such as IL-1β , IL-6, TNF-ɑ, and NO secretion [41].
These factors not only reduce the phagocytosis of microglia, but also trigger astrocytes to form a pro-inflammatory phenotype and increase the expression of pro-inflammatory factors [42].
Similarly, astrocyte activation contributes to microglial polarization
in AD.
When pathological products such as Aβ are stimulated, the NF-κB-related signaling pathway in astrocytes is activated, resulting in the release
of complement C3.
This activates C3 receptors on the surface of microglia and leads to impaired pro-inflammatory polarization and phagocytosis [43].
In short, inflammatory crosstalk between microglia and astrocytes occurs during the development and development of AD [44].
(2) Crosstalk between microglia and oligodendrocytes in AD
Oligodendrocytes, which play a key role in maintaining the function and integrity of axons and myelin, are also thought to be involved in AD [45].In a physiological state, oligodendrocytes are closely related to the production of steroids, substances that help protect neurons from damage caused by degenerative diseases [46].
Due to the neuroanti-inflammatory effect of steroids, the interaction between microglia and oligodendrocytes reduces neuroinflammation and prevents pro-inflammatory polarization
of microglia.
Similarly, increasing oligodendrocyte differentiation upregulates IGF-1 production [47], which is beneficial
for AD patients.
Although there are no experimental results to support the possible direct damage caused by Aβ or tau proteins to oligodendrocytes [48], some researchers have found too much Aβ or ApoE causes loss of myelin sheath integrity and induces oligodendrocyte apoptosis [49].
Previous studies have shown that oligodendrocytes may play an important role in the accumulation of tau protein in AD [50].
Single-cell sequencing techniques in the brains of AD patients reveal that oligodendrocytes exhibit the most individual variation among major brain cell types [51].
In addition, it has been hypothesized that inflammation reduces the ability of oligodendrocytes to form myelin [52].
These findings may shed light on new ideas for treating AD by interfering with communication between microglia and oligodendrocytes.
Since there has been a focus on the function of oligodendrocytes in maintaining myelin sheath integrity in the past, many studies have pointed to neuroinflammation-oriented diseases such as multiple sclerosis (MS).
Oligodendrocytes in AD are only seen as potential neuroprotective targets, so research into crosstalk dialogue between microglia and oligodendrocytes has just begun
.
(3) Crosstalk between AD microglia and neurons
The interaction between microglia and neurons plays an important role in the immune response throughout the development of AD [53].In a healthy brain, many molecules mediate two-way communication
between microglia and neurons.
On the one hand, neurons affect the function of microglia through neurotransmitters such as glutamic acid, dopamine, γ-aminobutyric acid (GABA), ADP, adenosine, and migration factors [54].
On the other hand, cytokines secreted by microglia such as GDNF and IGF-1 are also beneficial to maintain the physiological functions of neurons and play a key role in learning and memory [55].
。
Glutamate is the most important excitatory neurotransmitter in the CNS and is directly involved in crosstalk between microglia and neurons, and too much or too little glutamate release can have serious consequences for neurotransmission, leading to the development of AD [56].
However, under neuroinflammation and AD conditions, microglia tend to release excess glutamate, leading to neuronal excitotoxicity in AD and exacerbating neurodegenerative processes [57].
Cystine (Cys)/glutamate exchanger (Xc(-) exchanger), and d-serine release when stimulated by inflammation, directly affect the CNS glutamate levels in [58], which in turn affects the dialogue
between microglia and neurons.
Under conditions where AD persists chronic inflammation, the release of inflammatory factors such as TNF-α, IL-6, NO, and ROS increases neuronal death [59]
。 At the same time, the loss of homeostasis within microglia induces further release of pro-inflammatory factors and more neuronal death, leading to a vicious cycle [60].
As AD progresses, neurons are damaged
by an inflammatory environment induced by pro-inflammatory polarized microglia.
Due to the accumulation of Aβ, neurons themselves are induced to exhibit various pathological features [61]
.
Weakening of neuronal function, which in turn has a significant effect
on microglial polarization.
The interaction between microglia and neurons is like the two ends of a balancing beam, and damage at one end can wreak havoc on
the other.
The activation of microglia is not a single pro-inflammatory or anti-inflammatory polarization, but a series of changes such as differences in cell states or overlapping functions [62].
This may explain why as AD progresses, pro-inflammatory microglia increase, causing more neuronal death, leading to progressive clinical worsening
in AD patients.
(4) Crosstalk between microglia and peripheral innate immune cells in AD
There is growing evidence that peripheral immune cells enter the CNS through the damaged blood-brain barrier and then release cytokines such as IL-6, IL-1, and TNF-α [63]。 For example, T lymphocytes that migrate to the brains of AD patients are able to respond to Aβ [64].
In addition, various types of Aβ-specific T cells may promote enhanced Aβ clearance and weaken the inflammatory environment of the CNS, even reverse declining cognitive abilities [65]
。 In addition, in AD, specific crosstalk with microglia by peripherally recruited helper T lymphocytes by the production of the effector cytokine IFN-γ and activation of macrophages and CD8+ T cells to stimulate cells to respond
to harmful stimuli.
Currently, the specific mechanism of T helper lymphocyte function is unknown, although some researchers believe that in AD, helper T lymphocytes produce IFN-γ Helps microglia surround Aβ plaques and accelerate clearance [66].
However, it has also been suggested that T helper lymphocytes play an invasive role in AD, which leads to negative consequences through the common leukocyte recruitment process [67].
The exact role of cytotoxic T lymphocytes in the development of AD is unknown, but the infiltration observed in AD patients may indicate the involvement of cytotoxic T cells [68]
。 Thus, cytotoxic T cells and helper T lymphocytes appear to drive the development of AD and cause extra through crosstalk with microglia in chronic inflammation of AD CNS damage
.
IV.
Summary and Prospect
The results show that the dialogue between microglia and other cells in AD plays a key role
in CNS inflammation.
The dominant role of microglia in the inflammatory environment of AD and their interaction with other cells are reviewed
.
By exploring the mechanism of interaction between microglia and other cells, it provides a theoretical basis
for reducing neuroinflammation.
Reducing neuroinflammation is undoubtedly of great significance
for further research on nerve regeneration.
By regulating crosstalk between microglia and other cells, it may be possible to reduce neuronal death caused by inflammatory damage, while also providing a good environment
for the subsequent regeneration of new neurons.
In addition, since AD is often accompanied by disruption of the blood-brain barrier, it is difficult to predict crosstalk between innate cells and peripheral cells within the CNS, and whether these cells are beneficial to the treatment of AD remains controversial
.
The authors believe this review can provide researchers with new concepts
.
As Frozza et al.
point out, small advances in AD treatment strategies, even with a slight delay in the onset of onset, can reduce the overall burden of
disease.
Delaying the progression of AD by intervening in the polarization of microglia may pave the way for successful treatment of AD in the future
.
Original link: https://doi.
org/10.
4103/1673-5374.
355747
Funds: National Natural Science Foundation of China (81473577, 82004028), China Postdoctoral Science Foundation (2020M680912), Shanxi Provincial Applied Basic Research Program ( 201901D211538), Shanxi Provincial Department of Education Science and Technology Innovation Project for Colleges and Universities (2019L0734), Shanxi Provincial Health Commission Medical Science and Technology Leading Team (2020TD05), Shanxi Provincial Health Commission Key Laboratory of Neurological Disease Prevention and Control Research ( 2020SYS20), Shanxi University of Chinese Medicine Young Scientist Training Project (2021PY-QN-09) and Shanxi University of Traditional Chinese Medicine Discipline Construction Funding Project
.
First author: Master Wu Yige (left), Associate Professor Song Lijuan (middle), Corresponding author: Professor Ma Xinggen (right)
(Photo courtesy of: Neurobiology Research Center, Shanxi University of Chinese Medicine/Key Laboratory of Multiple Sclerosis and Blood Activation of the State Administration of Traditional Chinese Medicine)
Corresponding author and lab profile (swipe up and down to read).
Ma Xingen, Director of the Center/Research Office, Second-level Professor, PhD Supervisor, Subject Leader, Member of the Teaching Steering Committee of Traditional Chinese Medicine of the Ministry of Education; Vice Chairman of Zhongjing Inheritance and Innovation Professional Committee of the World Federation of Chinese Medicine Societies/Vice Chairman
of Zhongjing Academic Inheritance and Innovation Community of Chinese Society of Traditional Chinese Medicine.
His research direction is the prevention and treatment of central nervous system diseases
by combining traditional Chinese medicine and western medicine.
He has published more than 280 academic papers, including 212 Chinese core (or SCI) papers, and has been published by Immunol Res and Glia and other journal papers have been positively cited more than 2,000 times
.
The Neurobiology Research Center of Shanxi University of Chinese Medicine/Key Laboratory of Multiple Sclerosis and Qi and Blood Activation of the State Administration of Traditional Chinese Medicine is the key discipline
of the State Administration of Traditional Chinese Medicine 。 After years of construction, the discipline has gradually condensed and formed four stable research directions, namely the role and mechanism of combined traditional Chinese medicine and western medicine in the prevention and treatment of ischemic cerebrovascular diseases, the role and mechanism of integrated traditional Chinese and western medicine in the prevention and treatment of multiple sclerosis and other demyelinating diseases, the role and mechanism of integrated traditional Chinese medicine and western medicine in the prevention and treatment of Alzheimer's disease and vascular dementia, and the role and mechanism of
integrated traditional Chinese medicine in the prevention and treatment of Parkinson's disease and other movement disorders 。 These four directions are characterized by the prevention and treatment of the above diseases by the theory of traditional Chinese medicine.
Based on the pathological characteristics of neuroinflammation, oxidative stress and abnormal immune response as the basis of co-pathogenesis, the research advantage
of using the traditional theory of traditional Chinese medicine "treating different diseases together" has been formed.
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