Regulation of tau pathology by the microglial fractalkine receptor

Neuron. 2010 Oct 6;68(1):19-31. doi: 10.1016/j.neuron.2010.08.023.

Abstract

Aggregates of the hyperphosphorylated microtubule-associated protein tau (MAPT) are an invariant neuropathological feature of tauopathies. Here, we show that microglial neuroinflammation promotes MAPT phosphorylation and aggregation. First, lipopolysaccharide-induced microglial activation promotes hyperphosphorylation of endogenous mouse MAPT in nontransgenic mice that is further enhanced in mice lacking the microglial-specific fractalkine receptor (CX3CR1) and is dependent upon functional toll-like receptor 4 and interleukin-1 (IL-1) receptors. Second, humanized MAPT transgenic mice lacking CX3CR1 exhibited enhanced MAPT phosphorylation and aggregation as well as behavioral impairments that correlated with increased levels of active p38 MAPK. Third, in vitro experiments demonstrate that microglial activation elevates the level of active p38 MAPK and enhances MAPT hyperphosphorylation within neurons that can be blocked by administration of an interleukin-1 receptor antagonist and a specific p38 MAPK inhibitor. Taken together, our results suggest that CX3CR1 and IL-1/p38 MAPK may serve as novel therapeutic targets for human tauopathies.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • CX3C Chemokine Receptor 1
  • Cell Count / methods
  • Cells, Cultured
  • Coculture Techniques
  • Culture Media, Conditioned / pharmacology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Humans
  • Imidazoles / pharmacology
  • Lipopolysaccharides / pharmacology
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / chemistry
  • Microglia / drug effects
  • Microglia / metabolism*
  • Models, Biological
  • Neurons / drug effects
  • Neurons / physiology
  • Phosphorylation
  • Pyridines / pharmacology
  • Receptors, Chemokine / deficiency
  • Receptors, Chemokine / metabolism*
  • Receptors, Interleukin-1 / deficiency
  • Silver Staining / methods
  • Statistics, Nonparametric
  • Tauopathies / genetics
  • Tauopathies / metabolism*
  • Time Factors
  • Toll-Like Receptor 4 / deficiency
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • CX3C Chemokine Receptor 1
  • Culture Media, Conditioned
  • Cx3cr1 protein, mouse
  • Enzyme Inhibitors
  • Imidazoles
  • Lipopolysaccharides
  • MAPT protein, human
  • Pyridines
  • Receptors, Chemokine
  • Receptors, Interleukin-1
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • tau Proteins
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580