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Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in Alzheimer's disease brains.

ABSTRACT: The focus of this study is the expression of Toll-like receptor-3 (TLR-3), a receptor for double-stranded RNA, in human brains affected by Alzheimer's disease (AD) pathology. Toll-like receptors are a family of pattern recognition molecules primarily involved in host defenses to microbial pathogens, but roles in neurodegenerative disease have also been shown, as amyloid beta (A?) can be a ligand for TLR-2 and -4 and ?-synuclein for TLR-1 and TLR-2, while TLR-9 activation promotes A? removal. However, involvement of TLR-3 in AD has not been rigorously studied. Immunohistochemical analyses in human temporal cortical sections with a validated antibody for TLR-3 predominantly identified microglia, particularly strongly in cells associated with amyloid plaques, also brain vascular endothelial cells and subsets of astrocytes, but not neurons or p62-immunoreactive structures. Microglial TLR-3 colocalized with the endosomal/lysosomal marker CD68, which identifies phagocytic cells. Quantitative analyses of neuropathologically-staged human brain middle temporal gyrus samples using immunohistochemistry and mRNA expression methods demonstrated increased TLR-3 immunoreactivity and increased TLR-3 mRNA in AD compared to non-demented cases. There were significant positive correlations between TLR-3 mRNA levels and plaque or tangle loads in both series of samples. Increased expression of interferon beta (IFN-?) and interferon regulatory factor (IRF)-3 mRNA, two factors induced by TLR-3 signaling, were detected in the AD cases. Increased expression of TLR-4 and TLR-9 mRNA was also observed in these same samples, but not TLR-2. In vitro cultured human brain microglia responses to A? inflammatory activation were not altered by TLR-3 activation with activator polyinosinic;polycytidylic acid (poly I:C), while human brain endothelial cells showed reduction in responses when stimulated with both agents. Treatment of microglia with poly I:C did not increase their uptake and breakdown of A?.

SUBMITTER: Walker DG

PROVIDER: S-EPMC6151184 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in Alzheimer's disease brains.

Walker Douglas G DG Tang Tiffany M TM Lue Lih-Fen LF

Experimental neurology 20180801

The focus of this study is the expression of Toll-like receptor-3 (TLR-3), a receptor for double-stranded RNA, in human brains affected by Alzheimer's disease (AD) pathology. Toll-like receptors are a family of pattern recognition molecules primarily involved in host defenses to microbial pathogens, but roles in neurodegenerative disease have also been shown, as amyloid beta (Aβ) can be a ligand for TLR-2 and -4 and α-synuclein for TLR-1 and TLR-2, while TLR-9 activation promotes Aβ removal. How ...[more]

PMID: 30076830

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Project description:Multiple cellular systems exist to prevent uncontrolled inflammation in brain tissues; the suppressor of cytokine signaling (SOCS) proteins have key roles in these processes. SOCS proteins are involved in restricting cellular signaling pathways by enhancing the degradation of activated receptors and removing the stimuli for continued activation. There are eight separate SOCS genes that code for proteins with similar structures and properties. All SOCS proteins can reduce signaling of activated transcription factors Janus kinase (JAK) and signal transducer and activator of transcription (STAT), but they also regulate many other signaling pathways. SOCS-1 and SOCS-3 have particular roles in regulating inflammatory processes. Chronic inflammation is a key feature of the pathology present in Alzheimer's disease (AD)-affected brains resulting from responses to amyloid plaques or neurofibrillary tangles, the pathological hallmarks of AD. The goal of this study was to examine SOCS gene expression in human non-demented (ND) and AD brains and in human brain-derived microglia to determine if AD-related pathology resulted in a deficit of these critical molecules. We demonstrated that SOCS-1, SOCS-2, SOCS-3 and cytokine-inducible SH2 containing protein (CIS) mRNA expression was increased in amyloid beta peptide (A?)- and inflammatory-stimulated microglia, while SOCS-6 mRNA expression was decreased by both types of treatments. Using human brain samples from the temporal cortex from ND and AD cases, SOCS-1 through SOCS-7 and CIS mRNA and SOCS-1 through SOCS-7 protein could be detected constitutively in ND and AD human brain samples. Although, the expression of key SOCS genes did not change to a large extent as a result of AD pathology, there were significantly increased levels of SOCS-2, SOCS-3 and CIS mRNA and increased protein levels of SOCS-4 and SOCS-7 in AD brains. In summary, there was no evidence of a deficit of these key inflammatory regulating proteins in aged or AD brains.

Dataset Information

Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in Alzheimer's disease brains.

Publications

Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in Alzheimer's disease brains.

Similar Datasets

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