Regulation of tau pathology by the microglial fractalkine receptor

Kiran Bhaskar, Megan Konerth, Olga N. Kokiko-Cochran, Astrid Cardona, Richard M. Ransohoff, Bruce Lamb

Research output: Contribution to journalArticle

279 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)19-31
Number of pages13
JournalNeuron
Volume68
Issue number1
DOIs
StatePublished - Oct 6 2010
Externally publishedYes

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Microtubule-Associated Proteins
p38 Mitogen-Activated Protein Kinases
Pathology
Tauopathies
Interleukin-1 Receptors
Phosphorylation
Toll-Like Receptor 4
Interleukin-1
Transgenic Mice
Lipopolysaccharides
V28 receptor
Neurons

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Bhaskar, K., Konerth, M., Kokiko-Cochran, O. N., Cardona, A., Ransohoff, R. M., & Lamb, B. (2010). Regulation of tau pathology by the microglial fractalkine receptor. Neuron, 68(1), 19-31. https://doi.org/10.1016/j.neuron.2010.08.023

Regulation of tau pathology by the microglial fractalkine receptor. / Bhaskar, Kiran; Konerth, Megan; Kokiko-Cochran, Olga N.; Cardona, Astrid; Ransohoff, Richard M.; Lamb, Bruce.

In: Neuron, Vol. 68, No. 1, 06.10.2010, p. 19-31.

Research output: Contribution to journalArticle

Bhaskar, K, Konerth, M, Kokiko-Cochran, ON, Cardona, A, Ransohoff, RM & Lamb, B 2010, 'Regulation of tau pathology by the microglial fractalkine receptor', Neuron, vol. 68, no. 1, pp. 19-31. https://doi.org/10.1016/j.neuron.2010.08.023
Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb B. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. https://doi.org/10.1016/j.neuron.2010.08.023
Bhaskar, Kiran ; Konerth, Megan ; Kokiko-Cochran, Olga N. ; Cardona, Astrid ; Ransohoff, Richard M. ; Lamb, Bruce. / Regulation of tau pathology by the microglial fractalkine receptor. In: Neuron. 2010 ; Vol. 68, No. 1. pp. 19-31.
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