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

Exp Neurol. 2018 Nov:309:91-106. doi: 10.1016/j.expneurol.2018.07.016. Epub 2018 Aug 1.

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.

Keywords: Immunohistochemistry; Inflammation; Interferon responses; Microglia; Neuropathology; Phagocytosis; Plaques; Tangles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Brain / metabolism*
  • 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 Receptor 3 / metabolism*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism

Substances

  • AIF1 protein, human
  • Amyloid beta-Peptides
  • Calcium-Binding Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Microfilament Proteins
  • P62 protein, human
  • Peptide Fragments
  • RNA-Binding Proteins
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • amyloid beta-protein (1-42)
  • Phosphopyruvate Hydratase
  • Poly I-C