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Cited by 104Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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Microglia and Astrocytes in Alzheimer’s Disease: Significance and Summary of Recent Advances

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Deng, Qianting, Wu, Chongyun, Parker, Emily, Liu, Timon Cheng-Yi, Duan, Rui, Yang, Luodan·2023·Aging and disease
DOI 10.14336/ad.2023.0907PMC PMC11272214
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Abstract

Alzheimer's disease, one of the most common forms of dementia, is characterized by a slow progression of cognitive impairment and neuronal loss. Currently, approved treatments for AD are hindered by various side effects and limited efficacy. Despite considerable research, practical treatments for AD have not been developed. Increasing evidence shows that glial cells, especially microglia and astrocytes, are essential in the initiation and progression of AD. During AD progression, activated resident microglia increases the ability of resting astrocytes to transform into reactive astrocytes, promoting neurodegeneration. Extensive clinical and molecular studies show the involvement of microglia and astrocyte-mediated neuroinflammation in AD pathology, indicating that microglia and astrocytes may be potential therapeutic targets for AD. This review will summarize the significant and recent advances of microglia and astrocytes in the pathogenesis of AD in three parts. First, we will review the typical pathological changes of AD and discuss microglia and astrocytes in terms of function and phenotypic changes. Second, we will describe microglia and astrocytes' physiological and pathological role in AD. These roles include the inflammatory response, "eat me" and "don't eat me" signals, Aβ seeding, propagation, clearance, synapse loss, synaptic pruning, remyelination, and demyelination. Last, we will review the pharmacological and non-pharmacological therapies targeting microglia and astrocytes in AD. We conclude that microglia and astrocytes are essential in the initiation and development of AD. Therefore, understanding the new role of microglia and astrocytes in AD progression is critical for future AD studies and clinical trials. Moreover, pharmacological, and non-pharmacological therapies targeting microglia and astrocytes, with specific studies investigating microglia and astrocyte-mediated neuronal damage and repair, may be a promising research direction for future studies regarding AD treatment and prevention.

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Figure 1. Typical pathological changes in AD. (A) APP is cleaved by α-, β-, and γ-secretases. Under physiological conditions, APP is mainly cleaved by α-and γ-secretase, which generates a neurotrophic fragment, APPα, and a C-terminal fragment, C83. The C83 is cleaved into the nontoxic peptide P3 and APP intracellular domain (AICD) by γ-secretase. sAPPα and AICD support neurite outgrowth and the formation of learning and memory-related genes, providing neuroprotection for nerve cells. Under pathological conditions, APP is cleaved by β-secretase generating membrane-bound CTFβ fragment and N-terminal APPsβ. CTFβ fragment is then cleaved by γ secretase generating Aβ peptide and the AICD. (B) Tau, a microtubule-associated protein, acts as a stabilizer, promoting microtubule stabilization. Under physiological conditions, tau binds to microtubules and maintains cytoskeleton stability, microtubule structure, and neuronal transport. However, under pathological conditions, the abnormally phosphorylated tau protein dissociates from the neuronal microtubules. The detached phosphorylated tau forms paired helical filaments and develops into NFTs.
Figure 1. Typical pathological changes in AD. (A) APP is cleaved by α-, β-, and γ-secretases. Under physiological conditions, APP is mainly cleaved by α-and γ-secretase, which generates a neurotrophic fragment, APPα, and a C-terminal fragment, C83. The C83 is cleaved into the nontoxic peptide P3 and APP intracellular domain (AICD) by γ-secretase. sAPPα and AICD support neurite outgrowth and the formation of learning and memory-related genes, providing neuroprotection for nerve cells. Under pathological conditions, APP is cleaved by β-secretase generating membrane-bound CTFβ fragment and N-terminal APPsβ. CTFβ fragment is then cleaved by γ secretase generating Aβ peptide and the AICD. (B) Tau, a microtubule-associated protein, acts as a stabilizer, promoting microtubule stabilization. Under physiological conditions, tau binds to microtubules and maintains cytoskeleton stability, microtubule structure, and neuronal transport. However, under pathological conditions, the abnormally phosphorylated tau protein dissociates from the neuronal microtubules. The detached phosphorylated tau forms paired helical filaments and develops into NFTs.CC BY · PubMed Central
Figure 2. Schematic of microglia and astrocyte-mediated polarization. Microglia and astrocytes are usually classified into pro-inflammatory (M1/A1) or anti-inflammatory (M2/A2) phenotypes. The M1 and A1 are neurotoxic phenotypes releasing proinflammatory cytokines, including IL-12, IL-6, IL-23, TNF-α, IL-1β, IFNγ, IL-1α, and TNFα. The neuroprotective A2 and M2 phenotypes release anti-inflammatory cytokines, including IL-4, IL-10, IL-13, TGF-β, IL-4, and IL-10. Generally, during the early stage of AD, the resting microglia and astrocytes are polarized into the M2 and A2 phenotypes, secreting anti-inflammatory, and neuroprotective cytokines. However, during the late stage, the activated microglia and astrocytes are polarized into M1 and A1 phenotypes, secreting pro-inflammatory and neurotoxins cytokines.
Figure 2. Schematic of microglia and astrocyte-mediated polarization. Microglia and astrocytes are usually classified into pro-inflammatory (M1/A1) or anti-inflammatory (M2/A2) phenotypes. The M1 and A1 are neurotoxic phenotypes releasing proinflammatory cytokines, including IL-12, IL-6, IL-23, TNF-α, IL-1β, IFNγ, IL-1α, and TNFα. The neuroprotective A2 and M2 phenotypes release anti-inflammatory cytokines, including IL-4, IL-10, IL-13, TGF-β, IL-4, and IL-10. Generally, during the early stage of AD, the resting microglia and astrocytes are polarized into the M2 and A2 phenotypes, secreting anti-inflammatory, and neuroprotective cytokines. However, during the late stage, the activated microglia and astrocytes are polarized into M1 and A1 phenotypes, secreting pro-inflammatory and neurotoxins cytokines.CC BY · PubMed Central
Figure 3. Microglia and astrocyte-mediated “eat me” and “don’t eat me” signals. During development, the “eat me signal” is crucial for eliminating unnecessary or inappropriate synapses. This process involves the complement system (C1q, CR3, and C3) and PS mediated by microglia, MERTK, and MEGF10 mediated by astrocytes. However, the microglial SIRα mediated “don't eat me” signal is a negative synaptic pruning regulator to avoid excessive synapse loss.
Figure 3. Microglia and astrocyte-mediated “eat me” and “don’t eat me” signals. During development, the “eat me signal” is crucial for eliminating unnecessary or inappropriate synapses. This process involves the complement system (C1q, CR3, and C3) and PS mediated by microglia, MERTK, and MEGF10 mediated by astrocytes. However, the microglial SIRα mediated “don't eat me” signal is a negative synaptic pruning regulator to avoid excessive synapse loss.CC BY · PubMed Central
Figure 4. Microglia and astrocytes are involved in phagocytosis and remyelination. AD pathology leads to demyelination and fragmentation of myelin, consequently leading to the activation of microglia and astrocytes. These activated cells release pro-inflammatory factors (NOX4, ET-1) and upregulate the activity of CSF1R, Hsp60, NF-κB, and LCN2/LRP1, exacerbating myelin loss. However, activated microglia and astrocytes also promote TREM2, APOE, and QKI expressions, which support the clearance of myelin fragments and enhance remyelination.
Figure 4. Microglia and astrocytes are involved in phagocytosis and remyelination. AD pathology leads to demyelination and fragmentation of myelin, consequently leading to the activation of microglia and astrocytes. These activated cells release pro-inflammatory factors (NOX4, ET-1) and upregulate the activity of CSF1R, Hsp60, NF-κB, and LCN2/LRP1, exacerbating myelin loss. However, activated microglia and astrocytes also promote TREM2, APOE, and QKI expressions, which support the clearance of myelin fragments and enhance remyelination.CC BY · PubMed Central
Figure 5. Pharmacological and non-pharmacological treatments targeting microglia and astrocytes in AD. Pharmacological therapies, including galantamine, Vukazidibem, N-palmitoylethanolamide, Dihydroergotamine, Resveratrol, and non-pharmacological therapies, including exercise photobiomodulation, low-intensity pulsed ultrasound therapy, and deep brain stimulation, targeting glial cells have exhibited therapeutic potential in AD. Although recent studies have shown that transcranial magnetic stimulation (TMS) and transcranial alternating current stimulation (tACS), the other widely applied non-invasive treatment for brain diseases, have the potential to slow down AD progression, the impact of TMS and tACS on glial cells require further investigation.
Figure 5. Pharmacological and non-pharmacological treatments targeting microglia and astrocytes in AD. Pharmacological therapies, including galantamine, Vukazidibem, N-palmitoylethanolamide, Dihydroergotamine, Resveratrol, and non-pharmacological therapies, including exercise photobiomodulation, low-intensity pulsed ultrasound therapy, and deep brain stimulation, targeting glial cells have exhibited therapeutic potential in AD. Although recent studies have shown that transcranial magnetic stimulation (TMS) and transcranial alternating current stimulation (tACS), the other widely applied non-invasive treatment for brain diseases, have the potential to slow down AD progression, the impact of TMS and tACS on glial cells require further investigation.CC BY · PubMed Central

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Metadata

Authors
Deng, Q., Wu, C., Parker, E., Liu, T. C.-Y., Duan, R., & Yang, L.
Affiliations
  • South China Normal University (CN)
  • Augusta University (US)
Corresponding author
  • Duan, Rui
  • Yang, Luodan
ORCID
Venue
Aging and disease
Publisher
Aging and Disease
Published
2023
Volume
15
Issue
4
Pages
0
ISSN
2152-5250 (ISSN-L)
DOI
10.14336/ad.2023.0907
PMC
PMC11272214
OpenAlex
W4387196264
Cited by
102
References
302
Citations by year
2026: 38 · 2025: 43 · 2024: 21
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (32100918, 31971096, 31771256)
  • China Postdoctoral Science Foundation (2022 T150227, SL2022B04J00013)
  • National Key Research and Development Program of China (2017YFB0403801)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, microglia, astrocytes, neuroinflammation, reactive astrocytes, microglial activation, amyloid-beta, synaptic pruning, synaptic loss, remyelination, demyelination, neurodegeneration, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Humans, Microglia

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