Intramembrane attenuation of the TLR4-TLR6 dimer impairs receptor assembly and reduces microglia-mediated neurodegeneration

J Biol Chem. 2017 Aug 11;292(32):13415-13427. doi: 10.1074/jbc.M117.784983. Epub 2017 Jun 27.

Abstract

Recently, a single study revealed a new complex composed of Toll-like receptor 4 (TLR4), TLR6, and CD36 induced by fibrillary Aβ peptides, the hallmark of Alzheimer's disease. Unlike TLRs located on the plasma membrane that dimerize on the membrane after ligand binding to their extracellular domain, the TLR4-TLR6-CD36 complex assembly has been suggested to be induced by intracellular signals from CD36, similar to integrin inside-out signaling. However, the assembly site of TLR4-TLR6-CD36 and the domains participating in Aβ-induced signaling is still unknown. By interfering with TLR4-TLR6 dimerization using a TLR4-derived peptide, we show that receptor assembly is abrogated within the plasma membrane. Furthermore, we reveal that the transmembrane domains of TLR4 and TLR6 have an essential role in receptor dimerization and activation. Inhibition of TLR4-TLR6 assembly was associated with reduced secretion of proinflammatory mediators from microglia cells, ultimately rescuing neurons from death. Our findings support TLR4-TLR6 dimerization induced by Aβ. Moreover, we shed new light on TLR4-TLR6 assembly and localization and show the potential of inhibiting TLR4-TLR6 dimerization as a treatment of Alzheimer's disease.

Keywords: Alzheimer disease; CD36; TLR4; TLR6; amyloid-β; inflammation; microglia; neurodegenerative disease; neuroinflammation; toll-like receptor.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / immunology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • CD36 Antigens / chemistry
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism*
  • Cell Line
  • Cell Survival / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Fluorescence Resonance Energy Transfer
  • Immunoprecipitation
  • Ligands
  • Mice
  • Microglia / drug effects
  • Microglia / immunology
  • Microglia / metabolism*
  • Microglia / pathology
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Neurons / immunology
  • Neurons / metabolism*
  • Neurons / pathology
  • Nootropic Agents / chemistry
  • Nootropic Agents / metabolism
  • Nootropic Agents / pharmacology
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Protein Multimerization / drug effects
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / chemistry
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Toll-Like Receptor 6 / antagonists & inhibitors
  • Toll-Like Receptor 6 / chemistry
  • Toll-Like Receptor 6 / genetics
  • Toll-Like Receptor 6 / metabolism*

Substances

  • Amyloid beta-Peptides
  • CD36 Antigens
  • Ligands
  • Nerve Tissue Proteins
  • Nootropic Agents
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Tlr4 protein, mouse
  • Tlr6 protein, mouse
  • Toll-Like Receptor 4
  • Toll-Like Receptor 6