Role of toll-like receptor signalling in A uptake and clearance
Open accessAbstract
Deposits of amyloid beta-protein (Abeta) in neuritic plaques and cerebral vessels are a pathological hallmark of Alzheimer's disease. Fibrillar Abeta deposits are closely associated with inflammatory responses such as activated microglia in brain with this disease. Increasing lines of evidence support the hypothesis that activated microglia, innate immune cells in the CNS, play a pivotal role in the progression of the disease: either clearing Abeta deposits by phagocytic activity or releasing cytotoxic substances and pro-inflammatory cytokines. Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia. To investigate the role of TLR4 in the amyloidogenesis in vivo, we determined the amounts of cerebral Abeta in Alzheimer's disease mouse models with different genotypes of TLR4 using three distinct methods. We show that mouse models (Mo/Hu APPswe PS1dE9 mice) homozygous for a destructive mutation of TLR4 (Tlr(Lps-d)/Tlr(Lps-d)) had increases in diffuse and fibrillar Abeta deposits by immunocytochemistry, fibrillar Abeta deposits by thioflavine-S staining and buffer-soluble and insoluble Abeta by ELISA in the cerebrum, as compared with TLR4 wild-type mouse models. Although the differences in these parameters were less significant, mouse models heterozygous for the mutation (Tlr(Lps-d)/) showed co-dominant phenotypes. Consistent with these observations in vivo, cultured microglia d…
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TLR4 and several other TLRs are implicated in the clearance of Aβ deposits.
“TLR4 as well as several other TLRs are implicated in the clearance of Aβ deposits [125].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [125]
TLR 2, 4, and 9 signaling modulates phagocytosis and clearance of neurotoxic amyloid deposition in neurodegenerative diseases, perhaps by MyD88 independent signaling pathways.
“It has also been reported by others that TLR 2, 4, and 9 signaling modulates phacogytosis and clearance of neurotoxic amyloid deposition in neurodegenerative diseases, perhaps by MyD88 independent signaling pathways [43], [55].”
From MicroRNA 146a (miR-146a) Is Over-Expressed during Prion Disease and Modulates the Innate Immune Response and the Microglial Activation State (2012) · cites this paper as [55]
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- Authors
- Tahara, K., Kim, H.-D., Jin, J.-J., Maxwell, J. A., Li, L., & Fukuchi, K.-I.
- Affiliations
- Peoria campus of the University of Illinois System (US)
- University of Alabama (US)
- Corresponding author
- Tahara, K.
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-09-29
- Volume
- 129
- Issue
- 11
- Pages
- 3006-3019
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC2445613
- OpenAlex
- W2155965284
- Cited by
- 493
- References
- 12
- Citations by year
- 2026: 19 · 2025: 11 · 2024: 14 · 2023: 27 · 2022: 31 · 2021: 30 · 2020: 29 · 2019: 30 · 2018: 28 · 2017: 24 · 2016: 22 · 2015: 17 · 2014: 35 · 2013: 21 · 2012: 32
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Hewlett-Packard Development Company
- National Institutes of Health
- National Institute on Aging (R21AG025949, AG025949)
- National Institute of Neurological Disorders and Stroke (NS 43947, R01NS043947)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR4, amyloid-beta, Alzheimer's disease, microglia, amyloid clearance, innate immunity, APP/PS1 mice, TLR9 ligands, TLR2 ligands, neuroinflammation, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Genotype, Ligands, Mutation, Peptide Fragments, Blotting, Western, Signal Transduction, Amyloid beta-Peptides, Microglia, Toll-Like Receptor 4, Toll-Like Receptor 9, Mice, Presenilin-1
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