Cited by 352Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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Microglia in the Neuroinflammatory Pathogenesis of Alzheimer’s Disease and Related Therapeutic Targets

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Cai, Yongle, Liu, Jingliu, Wang, Bin, Sun, Miao, Yang, Hao·2022·Frontiers in Immunology

DOI 10.3389/fimmu.2022.856376PMC PMC9086828

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Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.

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Figure 1 The role of microglia in AD progression. The clearance of Aβ mediated by microglia contributes to the homeostasis maintenance of CNS. But, with the AD progression, excessive activation of microglia would release excessive pro-inflammatory factors to compromise neurons and their synapses.CC BY · PubMed Central

Figure 2 NLRP3 inflammasome and IDE in microglia of AD. The NLRP3 inflammasome accelerates microglial inflammation and can be inhibited by various substances. The secretion of IDE helps degrade Aβ and is regulated by diverse drugs.CC BY · PubMed Central

Figure 3 NF-κB pathway in microglia of AD. NF-κB signal pathway plays a central role in microglia-mediated neuroinflammation. This figure introduces multiple drugs mentioned in this review above, and their effects on microglia at length via NF-κB signal pathway.CC BY · PubMed Central

Figure 4 Microglial phagocytosis and autophagy in AD. Microglia eliminate Aβ load through phagocytosis and autophagy. This figure displays the regulatory mechanism of this process.CC BY · PubMed Central

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Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer’s disease mouse model
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“org 8 load and enhances Ab clearance, which mainly attributes to an increase in the ability of microglia to proliferate and the upregulation of phagocytosis-related genes caused by IL-1b (83).”
Background
Lipoxin A4 regulates microglial M1/M2 polarization after cerebral ischemia-reperfusion injury via the Notch signaling pathway
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Inhibitory Effects of Betulinic Acid on LPS-Induced Neuroinflammation Involve M2 Microglial Polarization via CaMKKβ-Dependent AMPK Activation
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Interleukin-10 deficiency exacerbates inflammation-induced tau pathology
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Microglia TREM2R47H Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels
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Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration
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Scavenger Receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer’s disease pathophysiology
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Interleukin-4 affects microglial autophagic flux
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CD36 Upregulation Mediated by Intranasal LV-NRF2 Treatment Mitigates Hypoxia-Induced Progression of Alzheimer's-Like Pathogenesis
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M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer’s Disease
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Authors: Cai, Y., Liu, J., Wang, B., Sun, M., & Yang, H.
Affiliations: First Affiliated Hospital of Soochow University (CN)
Corresponding author: Sun, Miao
Yang, Hao
ORCID: Wang, Bin
Sun, Miao
Yang, Hao
Venue: Frontiers in Immunology
Publisher: Frontiers Media SA
Published: 2022-04-26
Volume: 13
Pages: 856376-856376
ISSN: 1664-3224 (ISSN-L)
DOI: 10.3389/fimmu.2022.856376
PMC: PMC9086828
OpenAlex: W4281554374
Cited by: 351
References: 169
Citations by year: 2026: 70 · 2025: 148 · 2024: 88 · 2023: 41 · 2022: 4
FWCI: 7.24
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Frontiers in Immunology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (81,570,960, 81,974,244, 82071551, 2019YFA0802600)
Government of Jiangsu Province
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: microglia, Alzheimer's disease, neuroinflammation, neurodegeneration, amyloid-beta, tau hyperphosphorylation, neurofibrillary tangles, inflammatory cytokines, anti-inflammatory genes, phagocytosis, microglial homeostasis, therapeutic target
MeSH terms: Alzheimer Disease, Humans, Neurons, Amyloid beta-Peptides, Microglia, Neurodegenerative Diseases

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Microglia in the Neuroinflammatory Pathogenesis of Alzheimer’s Disease and Related Therapeutic Targets

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