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Cited by 136Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsImmune Response and Inflammation

Role of Toll Like Receptor 4 in Alzheimer’s Disease

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Calvo-Rodriguez, Maria, García-Rodríguez, Carmen, Villalobos, Carlos, Núñez, Lucía·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.01588PMC PMC7479089
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Abstract

Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer’s disease (AD). This view is supported, in part by data suggesting protection provided by selected non-steroidal anti-inflammatory drugs (NSAIDs). Additionally, molecular players of the innate immune system have been recently proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. TLR4 mediated signalling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proved to be key players in the pathology of AD. Among others, Aβo promote Ca2+ entry and mitochondrial Ca2+ overload leading to cell death in neurons. TLR4 has been recently involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a TLR4 receptor agonist, increases cytosolic Ca2+ concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were prevented significantly by pharmacological blockade of TLR4 receptor signalling. Moreover, TLR4 expression in rat hippocampal neurons increased significantly in aged neurons in vitro. Therefore, molecular patterns associated to infection and/or brain cell damage may activate TLR4 and Ca2+ signalling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of TLR4 in AD.

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  • RNA expression of TLR4 is increased in APP/PS1 mice and in brain tissue of patients with AD in association with plaque deposition.

    “RNA expression of TLR4 is increased in APP/PS1 mice and in brain tissue of patients with AD in association with plaque deposition [126, 127].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [127]

    The “TLR4 and Alzheimer’s Disease” section reports increased TLR4 gene expression in the cortex of APP/PS1 mice and in the frontal cortex of patients with AD relative to age-matched samples. It describes the mice as a model of cerebral amyloidosis, but does not establish that the increased RNA expression in either group is associated specifically with plaque deposition; page numbers are unavailable in our copy. (LLM, conf=0.83)

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Research works printed but not linked: 29

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Sorted by citations

Authors
Calvo-Rodriguez, M., García-Rodríguez, C., Villalobos, C., & Núñez, L.
Affiliations
Universidad de Valladolid (ES)
Corresponding author
Villalobos, Carlos
ORCID
Villalobos, Carlos
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-08-26
Volume
11
Pages
1588-1588
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.01588
PMC
PMC7479089
OpenAlex
W3080522152
Cited by
136
References
5
Citations by year
2026: 21 · 2025: 28 · 2024: 22 · 2023: 25 · 2022: 25 · 2021: 15
FWCI
1.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministerio de Ciencia e Innovación
  • Consejería de Educación, Junta de Castilla y León
  • BrightFocus Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
TLR4, Alzheimer's disease, neuroinflammation, innate immunity, amyloid-beta oligomers, lipopolysaccharide, calcium signaling, mitochondrial calcium overload, neuronal apoptosis, neuronal aging, hippocampal neurons, nonsteroidal anti-inflammatory drugs
MeSH terms
Aging, Alzheimer Disease, Animals, Calcium, Disease Susceptibility, Hippocampus, Humans, Amyloid beta-Peptides, Pyramidal Cells, Calcium Signaling, Toll-Like Receptor 4, Protein Aggregation, Pathological, Protein Aggregates

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