Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue
Abstract
Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE) in the regulation of both innate and adaptive immunity in different pathologies associated with neuroinflammation. In the present study we investigated the expression and cellular distribution of TLR2, TLR4, RAGE and their endogenous ligand high mobility group box 1 (HMGB1) in the spinal cord of control (n=6) and sporadic ALS (n=12) patients. The immunohistochemical analysis of TLR2, TLR4 and RAGE showed increased expression in reactive glial cells in both gray (ventral horn) and white matter of ALS spinal cord. TLR2 was predominantly detected in cells of the microglia/macrophage lineage, whereas the TLR4 and RAGE was strongly expressed in astrocytes. Real-time quantitative PCR analysis confirmed the increased expression of both TLR2 and TLR4 and HMGB1 mRNA level in ALS patients. In ALS spinal cord, HMGB1 signal is increased in the cytoplasm of reactive glia, indicating a possible release of this molecule from glial cells. Our findings show increased expression of TLR2, TLR4, RAGE and HMGB1 in reactive glia in human ALS spinal cord, suggesting activation of the TLR/RAGE signaling pathways. The activation of these pathways may contribute to the progression of inflammation, resulting in motor neuron injury. In this context, future studies, using animal models, will be important to achieve a better understanding of these signaling pathways in ALS in view of the development of new therapeutic strategies.
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Levels of RAGE and its ligands (e.g., AGEs) were increased in the spinal cord and cerebrospinal fluid of ALS patients.
“The levels of RAGE and its ligands (e.g., AGEs) were increased in the spinal cord and cerebrospinal fluid (CSF) of ALS patients.299,341”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [299]
Post-mortem tissue from sporadic ALS patients showed increased TLR4 expression in the spinal cord.
“An analysis of post-mortem tissue from sporadic ALS patients showed a increased TLR4 expression in the spinal cord,299”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [299]
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- Authors
- Casula, M., Iyer, A. M., Spliet, W. G. M., Anink, J. J., Steentjes, K., Sta, M., Troost, D., & Aronica, E.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- University Medical Center Utrecht (NL)
- Corresponding author
- Aronica, E.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 179
- Pages
- 233-243
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2069842601
- Cited by
- 200
- References
- 56
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 13 · 2023: 8 · 2022: 15 · 2021: 16 · 2020: 9 · 2019: 8 · 2018: 21 · 2017: 28 · 2016: 11 · 2015: 19 · 2014: 13 · 2013: 13 · 2012: 10
- FWCI
- 7.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- amyotrophic lateral sclerosis, TLR2, TLR4, receptor for advanced glycation end products, high mobility group box 1, neuroinflammation, reactive glia, microglia/macrophages, astrocytes, motor neuron injury, spinal cord, ventral horn
- MeSH terms
- Receptor for Advanced Glycation End Products, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Astrocytes, Female, Humans, Immunohistochemistry, Male, Middle Aged, Spinal Cord, Signal Transduction, In Situ Hybridization, Reverse Transcriptase Polymerase Chain Reaction, HMGB1 Protein, Toll-Like Receptor 2, Toll-Like Receptor 4
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