1. Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in Alzheimer's disease brains.
- Author
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Walker DG, Tang TM, and Lue LF
- Subjects
- Aged, Aged, 80 and over, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides pharmacology, Brain pathology, Calcium-Binding Proteins, Case-Control Studies, Cells, Cultured, Cytokines metabolism, DNA-Binding Proteins metabolism, Endothelial Cells drug effects, Gene Expression drug effects, Gene Expression physiology, HEK293 Cells, Humans, Microfilament Proteins, Microglia metabolism, Microglia pathology, Neuroglia metabolism, Neuroglia pathology, Peptide Fragments pharmacology, Phosphopyruvate Hydratase metabolism, Poly I-C pharmacology, RNA-Binding Proteins metabolism, Toll-Like Receptor 3 genetics, Toll-Like Receptors genetics, Toll-Like Receptors metabolism, Alzheimer Disease pathology, Brain metabolism, Toll-Like Receptor 3 metabolism
- 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 (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. 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-β) 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 Aβ 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 Aβ., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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