Cited by 389Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

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TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

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Yang, Junling, Wise, Leslie, Fukuchi, Ken-ichiro·2020·Frontiers in Immunology

DOI 10.3389/fimmu.2020.00724PMC PMC7190872

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Abstract

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

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Authors: Yang, J., Wise, L., & Fukuchi, K.-I.
Affiliations: Peoria campus of the University of Illinois System (US)
Corresponding author: Fukuchi, Ken-ichiro
ORCID: Yang, Junling
Venue: Frontiers in Immunology
Publisher: Frontiers Media SA
Published: 2020-04-23
Volume: 11
Pages: 724-724
ISSN: 1664-3224 (ISSN-L)
DOI: 10.3389/fimmu.2020.00724
PMC: PMC7190872
OpenAlex: W3019520705
Cited by: 387
References: 210
Citations by year: 2026: 64 · 2025: 73 · 2024: 72 · 2023: 73 · 2022: 67 · 2021: 30 · 2020: 7
FWCI: 4.41
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 Institutes of Health
National Institute on Aging (R21AG064811, R21AG056862, R21AG054937, R21AG062179, R21AG053719)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: Alzheimer's disease, TLR4, NLRP3 inflammasome, complement system, innate immunity, microglia, amyloid-beta, neurofibrillary tangles, neuroinflammation, synaptic loss, systemic inflammation, neurodegeneration, phagocytosis, synaptic pruning
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Alzheimer Disease, Animals, Complement System Proteins, Humans, Signal Transduction, Amyloid beta-Peptides, Toll-Like Receptor 4, Mice, Inflammasomes

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TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

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