Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain

Nicole Maphis, Guixiang Xu, Olga N. Kokiko-Cochran, Shanya Jiang, Astrid Cardona, Richard M. Ransohoff, Bruce T. Lamb, Kiran Bhaskar

Research output: Contribution to journalArticle

161 Scopus citations

Abstract

Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1-/-mice. Second, CD45+ microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1-/-mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.

Original languageEnglish (US)
Pages (from-to)1738-1755
Number of pages18
JournalBrain
Volume138
Issue number6
DOIs
StatePublished - Jun 1 2015

Keywords

  • Alzheimer's disease
  • Microglia
  • Neuroinflammation
  • Tau protein
  • Tauopathies

ASJC Scopus subject areas

  • Clinical Neurology

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    Maphis, N., Xu, G., Kokiko-Cochran, O. N., Jiang, S., Cardona, A., Ransohoff, R. M., Lamb, B. T., & Bhaskar, K. (2015). Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain, 138(6), 1738-1755. https://doi.org/10.1093/brain/awv081